Abstract:
A pharmaceutical composition includes, as active substance a mutated lentiviral ENV protein, substantially devoid of immunosuppressive properties or a variant of the mutated lentiviral ENV protein or a fragment of the above proteins, in association with a pharmaceutically acceptable carrier.

Description:
An attached Sequence Listing (i. Name: Replacement Sequence 0508-1306-1, ii. Date of Creation: Mar. 20, 2015, and iii. Size: 712 KB) is based on the disclosure of the Sequences in the present specification and figures. 
     FIELD OF THE INVENTION 
     The present invention relates to mutated lentiviral ENV proteins and their use as drugs. 
     BACKGROUND OF THE INVENTION 
     Lentivirus is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of genetic information into the DNA of the host cell and have the unique ability among retroviruses of being able to replicate in non-dividing cells, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses. 
     Human immunodeficiency virus (HIV) is according to WHO one of the most serious health crisis the world faces today. AIDS has killed more than 25 million people since 1981. In the most severely affected countries, the average life expectancy is now declining to 49 years of age—13 years less than in the absence of AIDS. According to UNAIDS an estimated number of 39.5 million people were living with HIV virus in 2006 and 4.3 million were infected in 2006. In many regions new infections are heavily concentrated in the younger generations (15-24 years of age). Access to treatment and care has greatly increased in recent years. Determining real time trends to HIV incidence and in particular the impact of prevention programmes ideally requires long studies of a large number of people. Given the practical difficulties of conducting such studies focus has been placed on young women and their infants. Children living with HIV typically acquire infection through a mother-to-child-transmission (MTCT), which occur during pregnancy, delivery or during breastfeeding. Renewed efforts are urgently required to increase access to comprehensive and integrated programs to prevent HIV infection in infants and young children, which will indicate a route to HIV-free generations. 
     There are two known types of HIV; HIV-1 and HIV-2 that infect humans. They belong to a group of retroviruses called Lentiviruses and a virus similar to HIV has been found in African monkeys. Retroviruses transfer their genes from a producer cell to a target cell as a genomic RNA transcript, which is reverse-transcribed after infection and integrated into the DNA genome of the target cell. 
     The first person with a documented HIV-infection died in 1959. In the early 1980s doctors in the US become aware, that more and more patients suffered from abnormal infections and showed signs of immune failure. The syndrome was named Acquired Immune Deficiency Syndrome (AIDS) and it was soon after discovered that HIV was the causative agent for the observed destruction of the immune system. Initially patients were offered a treatment based solely on pain relief and almost all inevitably died. In mid 1990s there were two important breakthroughs in treatment. Firstly, a new group of antiretroviral agents were discovered and secondly it became possible to measure the amount of HIV virus in blood. These two advances made it possible to treat patients with a combination of different agents and doctors were able to check, whether the treatment actually worked. The result was that the immune system of infected patients gradually became normal and patients lived longer. Today infected people in Western countries are having the same level of quality of life as those not infected and they are able to have children, although the economical and psychological consequences of having HIV are huge. The situation is, however, even more severe in developing countries, where more than 95% of those people infected with HIV/AIDS are living. Worldwide more than 25 million people have died from AIDS in the last 25 years. 
     Approximately 95% of the people who get infected today live in the developing countries, where expensive antiviral drugs are not available. Therefore, there is an urgent need for an effective vaccine—the only effective solution to the uncontrolled HIV pandemic. During the last few years research has brought up new knowledge on the fundamental biology of HIV-virus which is leading to new antiviral drugs and strategies for vaccine design. In spite of these substantial advances, an effective vaccine does not yet exist. Only attenuated (that is live but weakened) HIV-strains has been able to provide immunity in primate studies even though they will never reach a required safety profile suitable for mass vaccination. 
     The replication process for HIV-1 has an error rate of about one per 10,000 base pairs. Since the entire viral genome is just under 10,000 base pairs, it is estimated that on average one error is introduced into the HIV-1 genome at each viral replication cycle. 
     This high mutation rate contributes to extensive variability of the viruses inside any one person and an even wider variability across populations. 
     This variability has resulted in three HIV-1 variants being described, and the subspecies of virus called “clades.” The distinctions are based on the structure of the envelope proteins, which are especially variable. The M (for major) variant is by far the most prevalent world wide. Within the M variant are clades A, B, C, D, E, F, G, H, I, J and K, with clades A through E representing the vast majority of infections globally. Clades A, C and D are dominant in Africa, while clade B is the most prevalent in Europe, North and South America and Southeast Asia. Clades E and C are dominant in Asia. These clades differ by as much as 35%. Another variant is clade 0, which is observed in Cameroun isolates of HIV-1. The greatest variation in structure is seen in the envelope proteins gp120 and gp41. There are two important results from the very high mutation rate of HIV-1 that have profound consequences for the epidemic. First, the high mutation rate is one of the mechanisms that allow the virus to escape from control by drug therapies. These new viruses represent resistant strains. The high mutation rate also allows the virus to escape the patient&#39;s immune system by altering the structures that are recognized by immune components. An added consequence of this extensive variability is that the virus can also escape from control by vaccines, and therefore makes it difficult to find vaccines based on envelope proteins which are effective. 
     Moreover, the virus produces proteins having immunosuppressive properties, allowing to escape the patient&#39;s immune system survey. Thus, cell expressing such proteins become “invisible” to the immune system. 
     Consequently for a vaccine, there is a need to provide proteins as antigens having lost, or substantially lost, their immunosuppressive functions, in order to generate an efficient response. This will enable the individuals once infected by the virus to allow the immune system to destroy the infected cells and prevent/cure the infection. 
     Prior art has already intended to provide such proteins. 
     For instance, the international application WO 2005/095,442 (Inventors: Renard, Mangeney &amp; Heidmann) discloses mutations in the immunosuppressive domains of endogenous retroviruses (ERV) or onco retroviruses, such as HTLV or FeLV, ENV proteins. This document demonstrates that mutations at a specific position abolish the immunosuppressive properties of ENV proteins of ERV or onco retroviruses. However, the international application WO 2005/095, 442 never mentions or suggests that the mutations made in the immunosuppressive domain of ERV- or onco retroviruses ENV proteins can be transposable to lentiviral ENV proteins. 
     The international application WO 2010/022,740 discloses an extremely wide consensus sequence of a region of HIV ENV protein, described as follows:
         X(1-22)-C(23)-X(24-28)-C(29)-(X30-50)
 
wherein the amino acid residues of the consensus sequence are selected from the groups of residues consisting of:
 
X(1): L, S, R, P, F, A, V, M, and I; and
 
X(2): Q, R, K, H, L, M, and P; and
 
X(3): A, T, V, H, S, R, Q, G, M, and E; and
 
X(4): R, K, G, E, T, S, C, M, and H; and
 
X(5): V, I, L, D, A, S, F, M, and G; and
 
X(6): L, Q, V, M, P, W, T, and I; and
 
X(7): A, S, T, V, L, G, F, D, M, and E; and
 
X(8): V, L, I, M, A, W, K, G, and E; and
 
X(9): E, K, G, D, A, V, M, and F; and
 
X(10): X; and
 
X(11): Y, L, F, H, C, I, T, M, and N; and
 
X(12): L, I, V, M, Q, P, T, Y, and A; and
 
X(13): K, R, Q, G, S, E, H, W, T, V, M, N, Z, Y, A, P, and C; and
 
X(14): D, N, G, E, Y, V, S, H, A, M, and I; and
 
X(15): Q, R, H, K, P, L, M, and N; and
 
X(16): Q, K, R, T, H, E, S, P, M, and L; and
 
X(17): L, F, I, R, V, P, S, M, and H, and
 
X(18): L, M, P, I, H, and S; and
 
X(19): X; and
 
X(20): I, L, M, V, S, F, T, D, A, R, P, and J; and
 
X(21): W, R, G, F, L, M, and T; and
 
X(22): G, D, A, R, M, and C; and
 
X(24): X; and
 
X(25): G, R, E, N, A, M, and D; and
 
X(26): K, R, N, E, Q, T, S, I, M, and G; and
 
X(27): L, H, I, T, V, F, R, Q, S, P, A, J, M, and Y; and
 
X(28): I, V, T, L, R, F and M; and
 
X(30): T, P, Y, A, N, S, I, V, R, L, M, and H; and
 
X(31): T, S, P, N, M and I; and
 
X(32): A, N, T, S, D, R, FQ, P, I, E, V, M, L, K, H, C, and B; and
 
X(33): V, A, L, M, G, R, and C; and
 
X(34): X; and
 
X(35): W, R, G, L, M, and P; and
 
X(36): N, S, D, B, K, E, R, Q, M, and G; and
 
X(37): S, T, A, N, D, V, I, E, Y, K, L, R, G, P, M, F, W, H, Q, B, and C; and
 
X(38): S, T, N, I, G, R, L, C, A, W, M and E; and
 
X(39): W, G, A, R, E, C, Y, V, S, M, and H; and
 
X(40): X; and
 
X(41): N, G, K, S, D, E, T, R, H, P, A, B, V, Q, Y, M, and I; and
 
X(42): K, R, N, D, S, T, G, E, I, V, Y, Q, P, H, A, W, M, and C, and
 
X(43): S, T, N, K, I, R, D, E, P, L, A, W, G, M, H, Y, F, V, and C,
 
X(44): L, Y, Q, F, E, H, S, V, K, M, T, I, W, N, D, R, P, A, and G; and
 
X(45): D, E, N, S, T, K, G, L, A, Q, H, I, Y, B, R, V, P, M, F, W, Z, and C; and
 
X(46): E, D, Q, Y, K, N, T, S, A, W, H, M, R, I, G, L, V, Z, F, B, and P; and
 
X(47): I, D, E, M, G, T, Q, S, W, L, N, Y, K, V, R, F, A, P, and H, and
 
X(48): W, I, T, N, D, E, L, G, S, Y, R, V, K, H, A, Q, M, and F; and
 
X((49): D, N, E, G, W, Q, K, H, L, B, S, I, Y, T, A, R, M, Z, and V; and
 
X(50): N, D, T, K, S, H, L, G, E, W, I, Q, M, R, B, Y, P, and A;
       

     This consensus sequence contains 50 amino acids, in which the specific amino acids in position 10, 19, 24, 34 and 40 are defined as affecting the immunogenic properties of a HIV-1 envelope polypeptide, and the 45 remaining positions are randomly defined including the most common amino acids of wild-type HIV ENV proteins. 
     In fact, the teaching of WO 2010/022,740 is a transposition from endogenous retroviruses (ERV) or onco retroviruses to lentivirus on the basis of the teaching of WO 2005/095,442 (Inventors: Renard, Mangeney &amp; Heidmann), but said transposition is inappropriate in the case of lentivirus, as shown by the Inventor of the present invention. 
     Briefly speaking, Dr Heidmann is an Inventor in WO 2005/095,442 and in the present invention. As a matter of fact, the effects of the mutations described in WO 2005/095,442 were also tested in lentivirus by the Inventor of the present invention, but no effect was observed when the mutations identified in endogenous retroviruses or onco retroviruses were transposed into ENV protein of lentivirus. 
     Moreover, since any amino acid can be assigned to the positions 10, 19, 24, 34 or 40 in the consensus sequence, WO 2010/022,740 teaches that such mutations can be effective using any amino acid residue. This teaching is in contradiction with the present invention, showing that the immunosuppressive properties of HIV-1 ENV protein are only affected by specific mutations that are defined not only by their position, but also by the nature of the substituted amino acid residues. 
     Furthermore, WO 2010/022,740 discloses experimental results for only one specific mutation within the immunosuppressive domain of HIV ENV protein, as defined by the 50 amino acids consensus sequence. The mutation, a substitution by R as the only one exemplified in the international application WO 2010/022,740, occurs at the amino acid in position 19, which again is equivalent to the position disclosed in the international application WO 2005/095,442 if one simply aligns ENV sequences (see FIG. 3 in WO 2010/022,740, which is a copy of FIG. 3 in Benit et al. 2001 , Journal of Virology , Vol. 75, No. 23, p. 11709-11719) (Of note not only the position of the amino acid, but also the nature of the substitution (by arginine) is similar to the one described in WO 2005/095,442). 
     More specifically, when aligning the ENV sequences respectively of an endogenous retrovirus or onco retrovirus and a lentivirus, according to FIG. 3 of Benit et al.: 
                                
it appears that the position 19 in lentivirus corresponds to the position in WO 2005/095,442 where a specific substitution into arginine, E-R for endogenous or onco retrovirus, results in loss of immunosuppressive activity.
 
     The international application WO 2010/022,740 discloses that said mutated HIV ENV protein inhibits proliferation of PBMC ex vivo, but such ex vivo result has no in vivo predictive value. 
     However, WO 2010/022,740 never discloses or suggests that mutants are efficient in vivo, i.e. that cell expressing mutants are detected by the immune system. 
     Moreover, as disclosed hereafter, such mutations are not efficient in vivo. Indeed, results disclosed hereafter in the example section relative to the present invention demonstrate that said substitution G19R does not inhibit in vivo the immunosuppressive properties of the ENV protein. 
     As a consequence, WO 2010/022,740 raises the same technical problem as the present invention, but does not offer an appropriate technical solution. This prior art reveals the difficulties to overcome the identification of the effective mutations affecting the immunosuppressive properties of the lentiviral ENV proteins. 
     Thus, the provision of in vivo effective non immunosuppressive lentiviral ENV proteins remains. 
     SUMMARY OF THE INVENTION 
     One aim of the invention is to provide new mutated ENV proteins devoid of immunosuppressive properties. 
     Another aim of the invention is to provide a new pharmaceutical composition efficient for treating lentiviral infection. 
     Another aim of the invention is to provide an efficient vaccine. 
     The invention relates to a pharmaceutical composition comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein having at least 70% identity, preferably at least 80% identity, to one sequence chosen from the group consisting of SEQ ID NO: 216, SEQ ID NO: 420 and SEQ ID NO: 421,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, F, G, L, R or deleted, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W 
             or Y, or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G, R or deleted, 
             or 
             X a  is A, F, G, L, R or deleted, and X b  is A, F, G, R or deleted, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence: 
           
         
       
    
     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, F, G, L, R or deleted, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W 
             or Y, or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G, R or deleted, 
             or 
             X a  is A, F, G, L, R or deleted, and X b  is A, F, G, R or deleted, 
             in association with a pharmaceutically acceptable carrier, 
             said substantial absence of immunosuppressive activity of the above mentioned mutated human or simian lentiviral ENV protein or of the above defined fragment being liable to be assessed by the fact that in an in vivo assay involving engrafted tumor cells rejection, 
             said tumor cells being transduced either so as to express said mutated ENV protein or said fragment (“mutated ENV tumor cells”), 
             or said tumor cells being transduced so as to express said wild type ENV protein or a fragment thereof (“wild type ENV tumor cells”), 
             or said tumor cells being not transduced (“normal tumor cells”), the following ratio: 
             immunosuppression index of said mutated ENV protein or of said fragment (i mutated env )/immunosuppression index of wild type ENV protein (i wild type env ) is less than 0.5, 
             i mutated env  being defined by: (maximum area reached by mutated ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells), and 
             i wild type env  being defined by: (maximum area reached by wild type ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells). 
           
         
       
    
     The present application is based on the unexpected observation made by the Inventors that some specific amino acids of the immunosuppressive domain of a lentiviral ENV protein can be mutated conferring to said lentiviral ENV protein essentially no immunosuppressive properties, or no immunosuppressive properties, while retaining its antigenicity, the three-dimentional structure of the immunosuppressive domain, and its expression at the plasma membrane. Moreover, the mutated lentiviral ENV protein according to the invention does not alter the infectivity of a virus expressing it. 
     In the invention, the “mutated simian or human lentiviral ENV proteins” means that the ENV proteins derive from the expression of an env gene of a lentivirus of human or simian. 
     Lentiviruses according to the invention encompassed by the invention are HIV-1 and 2 and Simian immunodeficiency virus (SIV). 
     Because of the high mutation rate of HIV-1, HIV-2 and SIV viruses, the “mutated ENV protein”, as defined in the invention, encompasses two meanings. 
     According to the first meaning, the said “mutated ENV protein” is the unnatural result of the intervention of human beings. 
     According to the second meaning, the mutated ENV protein also encompasses naturally occurring variants for which up to now the non immunosuppressive properties remain unknown. 
     This second meaning takes into consideration the natural variability of HIV and SIV variants inside a same infected individual, wherein the said “mutated ENV protein” might be non immunosuppressive but its property is undetectable because an HIV infected patient always carries many HIV variants, the majority of which is immunosuppressive. 
     The three following proteins correspond to wild type sequences of the ENV protein of HIV-1, HIV-2 and SIV respectively. In the invention, they are considered as reference sequences of wild type ENV proteins. 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 SEQ ID NO: 417 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEK 
               
               
                 wild type HIV-1 
                 LWVTVYYGVPVWKEATTTLFCASDAKAYDTEVH 
               
               
                   
                 NVWATHACVPTDPNPQEVVLVNVTENFNMWKND 
               
               
                   
                 MVEQMHEDIISLWDQSLKPCVKLTPLCVSLKCT 
               
               
                   
                 DLGNATNTNSSNTNSSSGEMMMEKGEIKNCSFN 
               
               
                   
                 ISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTL 
               
               
                   
                 TSCNTSVITQACPKVSFEPIPIHYCAPAGFAIL 
               
               
                   
                 KCNNKTFNGTGPCTNVSTVQCTHGIRPVVSTQLL 
               
               
                   
                 LNGSLAEEEVVIRSANFTDNAKTIIVQLNQSVE 
               
               
                   
                 INCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMR 
               
               
                   
                 QAHCNISRAKWNATLKQIASKLREQFGNNKTII 
               
               
                   
                 FKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFI 
               
               
                   
                 NMWQEVGKAMYAPPISGQIRCSSNITGLLLTRD 
               
               
                   
                 GGNNNNGSEIFRPGGGDMRDNWRSELYKYKV 
               
               
                   
                 VKIEPLGVAPTKAKRRVVQREKRAVGIGALFLG 
               
               
                   
                 FLGAAGSTMGARSMTLTVQARQLLSGIVQQQN 
               
               
                   
                 NLLRAIEAQQHLLQLTVWGIKQLQARILAVERYL 
               
               
                   
                 KDQQLLGIWGCSGKLICTTAVPWNASWSNKSL 
               
               
                   
                 EQIWNNMTWMEWDREINNYTSLIHSLIEESQNQ 
               
               
                   
                 QEKNEQELLELDKWASLWNWFNITNWLWYIKIF 
               
               
                   
                 IMIVGGLVGLRIVFAVLSIVNRVRQGYSPLSFQ 
               
               
                   
                 THLPTPRGPDRPEGIEEEGGERDRDRSIRLVN 
               
               
                   
                 GSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVE 
               
               
                   
                 LLGRRGWEALKYWWNLLQYWSQELKNSAVSLL 
               
               
                   
                 NATAIAVAEGTDRVIEVVQGACRAIRHIPRRIRQ 
               
               
                   
                 GLERILL 
               
               
                   
               
               
                 SEQ ID NO: 418 
                 MCGRNQLFVASLLASACLIYCVQYVTVFYGVPV 
               
               
                 Wild type HIV-2 
                 WRNASIPLFCATKNRDTWGTIQCLPDNDDYQEI 
               
               
                   
                 ALNVTEAFDAWNNTVTEQAVEDVWSLFETSIKP 
               
               
                   
                 CVKLTPLCVAMRCNSTTAKNTTSTPTTTTTANT 
               
               
                   
                 TIGENSSCIRTDNCTGLGEEEMVDCQFNMTGLE 
               
               
                   
                 RDKKKLYNETWYSKDVVCESNDTKKEKTCYMNH 
               
               
                   
                 CNTSVITESCDKHYWDTMRFRYCAPPGFALLRC 
               
               
                   
                 NDTNYSGFEPNCSKVVAATCTRMMETQTSTWFG 
               
               
                   
                 FNGTRAENRTYIYWHGRDNRTIISLNKFYNLTVH 
               
               
                   
                 CKRPGNKTVVPITLMSGLVFHSQPINRRPRQA 
               
               
                   
                 WCWFKGEWKEAMKEVKLTLAKHPRYKGTNDTEK 
               
               
                   
                 IRFIAPGERSDPEVAYMWTNCRGEFLYCNMTWFL 
               
               
                   
                 NWVENRTNQTQHNYVPCHIKQIINTWHKVGKNV 
               
               
                   
                 YLPPREGQLTCNSTVTSIIANIDGGENQTNITFS 
               
               
                   
                 AEVAELYRLELGDYKLIEVTPIGFAPTPVKRYSS 
               
               
                   
                 APVRNKRGVFVLGFLGFLTTAGAAMGAASLTL 
               
               
                   
                 SAQSRTLLAGIVQQQQQLLDVVKRQQEMLRLT 
               
               
                   
                 VWGTKNLQARVTAIEKYLKDQAQLNSWGCAFR 
               
               
                   
                 QVCHTTVPWVNDTLTPDWNNMTWQEWEQRIR 
               
               
                   
                 NLEANISESLEQAQIQQEKNMYELQKLNSWDVF 
               
               
                   
                 GNWFDLTSWIKYIQYGVYIVVGIIVLRIVIYVVQ 
               
               
                   
                 MLSRLRKGYRPVFSSPPAYFQQIHIHKDREQPA 
               
               
                   
                 REETEEDVGNSVGDNWWPWPIRYIHFLIRQLIRL 
               
               
                   
                 LNRLYNICRDLLSRSFQTLQLISQSLRRALTAVR 
               
               
                   
                 DWLRFNTAYLQYGGEWIQEAFRAFARATGETLT 
               
               
                   
                 NAWRGFWGTLGQIGRGILAVPRRIRQGAEIALL 
               
               
                   
               
               
                 SEQ ID NO: 419 
                 MGCLGNQLLIAILLLSVYGIYCTLYVTVFYGVP 
               
               
                 wild type SIV 
                 AWRNATIPLFCATKNRDTWGTTQCLPDNGDYSE 
               
               
                 mac239 
                 VALNVTESFDAWNNTVTEQAIEDVWQLFETSIK 
               
               
                   
                 PCVKLSPLCITMRCNKSETDRWGLTKSITTTA 
               
               
                   
                 STTSTTASAKVDMVNETSSCIAQDNCTGLEQE 
               
               
                   
                 QMISCKFNMTGLKRDKKKEYNETWYSADLVCEQ 
               
               
                   
                 GNNTGNESRCYMNHCNTSVIQESCDKHYWDAIR 
               
               
                   
                 FRYCAPPGYALLRCNDTNYSGFMPKCSKVVVSS 
               
               
                   
                 CTRMMETQTSTWFGFNGTRAENRTYIYWHGRDN 
               
               
                   
                 RTIISLNKYYNLTMKCRRPGNKTVLPVTIMSGLV 
               
               
                   
                 FHSQPINDRPKQAWCWFGGKWKDAIKEVKQTIV 
               
               
                   
                 KHPRYTGTNNTDKINLTAPGGGDPEVTFMWTNCR 
               
               
                   
                 GEFLYCKMNWFLNWVEDRNTANQKPKEQHKRN 
               
               
                   
                 YVPCHIRQIINTWHKVGKNVYLPPREGDLTCNS 
               
               
                   
                 TVTSLIANIDWIDGNQTNITMSAEVAELYRLELG 
               
               
                   
                 DYKLVEITPIGLAPTDVKRYTTGGTSRNKRGVF 
               
               
                   
                 VLGFLGFLATAGSAMGAASLTLTAQSRTLLAGI 
               
               
                   
                 VQQQQQLLDVVKRQQELLRLTVWGTKNLQTR 
               
               
                   
                 VTAIEKYLKDQAQLNAWGCAFRQVCHTTVPW 
               
               
                   
                 PNASLTPKWNNETWQEWERKVDFLEENITALL 
               
               
                   
                 EEAQIQQEKNMYELQKLNSWDVFGNWFDLAS 
               
               
                   
                 WIKYIQYGVYIVVGVILLRIVIYIVQMLAKLRQ 
               
               
                   
                 GYRPVFSSPPSYFQQTHIQQDPALPTREGK 
               
               
                   
                 ERDGGEGGGNSSWPWQIEYIHFLIRQLIRLLTW 
               
               
                   
                 LFSNCRTLLSRVYQILQPILQRLSATLQRIREV 
               
               
                   
                 LRTELTYLQYGWSYFHEAVQAVWRSATETLAGA 
               
               
                   
                 WGDLWETLRRGGRWILAIPRRIRQGLELTLL 
               
               
                   
               
             
          
         
       
     
     Variant in the invention encompasses SIV, HIV-1 and HIV-2 ENV proteins. 
     Variants of the HIV-1 mutated ENV proteins according to the invention have at least 70%, preferably at least 80%, more preferably at least 90% of identity with the wild type amino acid sequence of the HIV-1 ENV protein, and comprises the mutations as described above, and harbour no immunosuppressive activity. 
     Variants of the HIV-2 mutated ENV proteins according to the invention have at least 70%, preferably at least 80%, more preferably at least 90% of identity with the wild type amino acid sequence of the HIV-2 ENV protein, and comprises the mutations as described above, and harbour no immunosuppressive activity. 
     Variants of the SIV mutated ENV proteins according to the invention have at least 70%, preferably at least 80%, more preferably at least 90% of identity with the wild type amino acid sequence of the SIV ENV protein, and comprises the mutations as described above, and harbour no immunosuppressive activity. 
     The three following proteins (SEQ ID NO: 216, 420 and 421) correspond to three mutated sequences of the ENV protein of HIV-1, HIV-2 and SIV respectively. In the invention, they are considered as reference sequences of the mutated ENV proteins. 
     More specifically, SEQ ID NO: 216 corresponds to the SEQ ID NO: 417 in which the amino acid residue Y in position 5 (X a ) of the sequence A-[I/V]-E-[K/R]-X a -X b -X-D-Q has been substituted by R. 
     SEQ ID NO: 420 corresponds to the SEQ ID NO: 418 in which the amino acid residue Y in position 5 (X a ) of the sequence A-[I/V]-E-[K/R]-X a -X b -X-D-Q has been substituted by R. 
     SEQ ID NO: 421 corresponds to the SEQ ID NO: 419 in which the amino acid residue Y in position 5 (X a ) of the sequence A-[I/V]-E-[K/R]-X a -X b -X-D-Q has been substituted by R. 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 SEQ ID NO: 216 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEK 
               
               
                 mutated HIV-1 
                 LWVTVYYGVPVWKEATTTLFCASDAKAYDTEVH 
               
               
                   
                 NVWATHACVPTDPNPQEVVLVNVTENFNMWKND 
               
               
                   
                 MVEQMHEDIISLWDQSLKPCVKLTPLCVSLKCT 
               
               
                   
                 DLGNATNTNSSNTNSSSGEMMMEKGEIKNCSFN 
               
               
                   
                 ISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTL 
               
               
                   
                 TSCNTSVITQACPKVSFEPIPIHYCAPAGFAI 
               
               
                   
                 LKCNNKTFNGTGPCTNVSTVQCTHGIRPVV 
               
               
                   
                 STQLLLNGSLAEEEVVIRSANFTDNAKTIIVQ 
               
               
                   
                 LNQSVEINCTRPNNNTRKSIRIQRGPGRAFV 
               
               
                   
                 TIGKIGNMRQAHCNISRAKWNATLKQIASKL 
               
               
                   
                 REQFGNNKTIIFKQSSGGDPEIVTHSFNCGG 
               
               
                   
                 EFFYCNSTQLFNSTWFNSTWSTEGSNNTEGS 
               
               
                   
                 DTITLPCRIKQFINMWQEVGKAMYAPPISGQIR 
               
               
                   
                 CSSNITGLLLTRDGGNNNNGSEIFRPGGGDM 
               
               
                   
                 RDNWRSELYKYKVVKIEPLGVAPTKAKRRVV 
               
               
                   
                 QREKRAVGIGALFLGFLGAAGSTMGARSMTL 
               
               
                   
                 TVQARQLLSGIVQQQNNLLRAIEAQQHLLQLT 
               
               
                   
                 VWGIKQLQARILAVER R LKDQQLLGIWGCSG 
               
               
                   
                 KLICTTAVPWNASWSNKSLEQIWNNMTWME 
               
               
                   
                 WDREINNYTSLIHSLIEESQNQQEKNEQELLE 
               
               
                   
                 LDKWASLWNWFNITNWLWYIKIFIMIVGGLVG 
               
               
                   
                 LRIVFAVLSIVNRVRQGYSPLSFQTHLPTPRG 
               
               
                   
                 PDRPEGIEEEGGERDRDRSIRLVNGSLALIW 
               
               
                   
                 DDLRSLCLFSYHRLRDLLLIVTRIVELLGRRG 
               
               
                   
                 WEALKYWWNLLQYWSQELKNSAVSLLNAT 
               
               
                   
                 AIAVAEGTDRVIEVVQGACRAIRHIPRRIRQG 
               
               
                   
                 LERILL 
               
               
                   
               
               
                 SEQ ID NO: 420 
                 MCGRNQLFVASLLASACLIYCVQYVTVFYGVPV 
               
               
                 mutated HIV-2 
                 WRNASIPLFCATKNRDTWGTIQCLPDNDDYQEI 
               
               
                   
                 ALNVTEAFDAWNNTVTEQAVEDVWSLFETSIKP 
               
               
                   
                 CVKLTPLCVAMRCNSTTAKNTTSTPTTTTTANT 
               
               
                   
                 TIGENSSCIRTDNCTGLGEEEMVDCQFNMTGLER 
               
               
                   
                 DKKKLYNETWYSKDVVCESNDTKKEKTCYMN 
               
               
                   
                 HCNTSVITESCDKHYWDTMRFRYCAPPGFALL 
               
               
                   
                 RCNDTNYSGFEPNCSKVVAATCTRMMETQTS 
               
               
                   
                 TWFGFNGTRAENRTYIYWHGRDNRTIISLNKFYN 
               
               
                   
                 LTVHCKRPGNKTVVPITLMSGLVFHSQPINRRP 
               
               
                   
                 RQAWCWFKGEWKEAMKEVKLTLAKHPRYKG 
               
               
                   
                 TNDTEKIRFIAPGERSDPEVAYMWTNCRGEFL 
               
               
                   
                 YCNMTWFLNWVENRTNQTQHNYVPCHIKQIINT 
               
               
                   
                 WHKVGKNVYLPPREGQLTCNSTVTSIIANIDGG 
               
               
                   
                 ENQTNITFSAEVAELYRLELGDYKLIEVTPIGFA 
               
               
                   
                 PTPVKRYSSAPVRNKRGVFVLGFLGFLTTAGA 
               
               
                   
                 AMGAASLTLSAQSRTLLAGIVQQQQQLLDVVK 
               
               
                   
                 RQQEMLRLTVWGTKNLQARVTAIEK R LKDQAQ 
               
               
                   
                 LNSWGCAFRQVCHTTVPWVNDTLTPDWNNM 
               
               
                   
                 TWQEWEQRIRNLEANISESLEQAQIQQEKNMY 
               
               
                   
                 ELQKLNSWDVFGNWFDLTSWIKYIQYGVYIVVG 
               
               
                   
                 IIVLRIVIYVVQMLSRLRKGYRPVFSSPPAYFQ 
               
               
                   
                 QIHIHKDREQPAREETEEDVGNSVGDNWWPWP 
               
               
                   
                 IRYIHFLIRQLIRLLNRLYNICRDLLSRSFQTL 
               
               
                   
                 QLISQSLRRALTAVRDWLRFNTAYLQYGGEW 
               
               
                   
                 IQEAFRAFARATGETLTNAWRGFWGTLGQIG 
               
               
                   
                 RGILAVPRRIRQGAEIALL 
               
               
                   
               
               
                 SEQ ID NO: 421 
                 MGCLGNQLLIAILLLSVYGIYCTLYVTVFYGVP 
               
               
                 mutated SIV 
                 AWRNATIPLFCATKNRDTWGTTQCLPDNGDYSE 
               
               
                 mac239 
                 VALNVTESFDAWNNTVTEQAIEDVWQLFETSIK 
               
               
                   
                 PCVKLSPLCITMRCNKSETDRWGLTKSITTTAS 
               
               
                   
                 TTSTTASAKVDMVNETSSCIAQDNCTGLEQEQ 
               
               
                   
                 MISCKFNMTGLKRDKKKEYNETWYSADLVCE 
               
               
                   
                 QGNNTGNESRCYMNHCNTSVIQESCDKHYW 
               
               
                   
                 DAIRFRYCAPPGYALLRCNDTNYSGFMPKCS 
               
               
                   
                 KVVVSSCTRMMETQTSTWFGFNGTRAENRT 
               
               
                   
                 YIYWHGRDNRTIISLNKYYNLTMKCRRPGNKTV 
               
               
                   
                 LPVTIMSGLVFHSQPINDRPKQAWCWFGGK 
               
               
                   
                 WKDAIKEVKQTIVKHPRYTGTNNTDKINLTAP 
               
               
                   
                 GGGDPEVTFMWTNCRGEFLYCKMNWFLNW 
               
               
                   
                 VEDRNTANQKPKEQHKRNYVPCHIRQIINTW 
               
               
                   
                 HKVGKNVYLPPREGDLTCNSTVTSLIANIDWI 
               
               
                   
                 DGNQTNITMSAEVAELYRLELGDYKLVEITPIG 
               
               
                   
                 LAPTDVKRYTTGGTSRNKRGVFVLGFLGFL 
               
               
                   
                 ATAGSAMGAASLTLTAQSRTLLAGIVQQQQQ 
               
               
                   
                 LLDVVKRQQELLRLTVWGTKNLQTRVTAIEK 
               
               
                   
                   R LKDQAQLNAWGCAFRQVCHTTVPWPNAS 
               
               
                   
                 LTPKWNNETWQEWERKVDFLEENITALLEE 
               
               
                   
                 AQIQQEKNMYELQKLNSWDVFGNWFDLAS 
               
               
                   
                 WIKYIQYGVYIVVGVILLRIVIYIVQMLAKLRQ 
               
               
                   
                 GYRPVFSSPPSYFQQTHIQQDPALPTREGKER 
               
               
                   
                 DGGEGGGNSSWPWQIEYIHFLIRQLIRLLTW 
               
               
                   
                 LFSNCRTLLSRVYQILQPILQRLSATLQRIRE 
               
               
                   
                 VLRTELTYLQYGWSYFHEAVQAVWRSATE 
               
               
                   
                 TLAGAWGDLWETLRRGGRWILAIPRRIRQG 
               
               
                   
                 LELTLL 
               
               
                   
               
             
          
         
       
     
     The invention also encompasses the variants of the “mutated simian or human lentiviral ENV protein”, harbouring the above mentioned mutations, and conferring a lack of immunosuppressive properties to said variant. 
     Variants of the HIV-1 mutated ENV proteins according to the invention have at least 70%, preferably at least 80%, more preferably at least 90% of identity with the reference mutated sequence of HIV-1 ENV protein (SEQ ID NO: 216), and comprises the mutations as described above, and harbour no immunosuppressive activity. 
     Variants of the HIV-2 mutated ENV proteins according to the invention have at least 70%, preferably at least 80%, more preferably at least 90% of identity with the reference mutated sequence of the HIV-2 ENV protein (SEQ ID NO: 420), and comprises the mutations as described above, and harbour no immunosuppressive activity. 
     Variants of the SIV mutated ENV proteins according to the invention have at least 70%, preferably at least 80%, more preferably at least 90% of identity with the reference mutated sequence of the SIV ENV protein (SEQ ID NO: 421), and comprises the mutations as described above, and harbour no immunosuppressive activity. 
     The immunosuppressive domain (ISU) of the lentivirus according to the invention can be delimited by the sequence SEQ ID NO: 6, 
                           (SEQ ID NO: 6)            x GIVQQQ xx LL xxxxxx Q xx L x L xx WG x K x LQ x R xx A [I/V] E [K/R] Y           L x DQ xx Lx              
in which x represents any amino acid.
 
     SEQ ID NO: 6 corresponds to the non mutated ISU domain. 
     In this SEQ ID NO: 6, “x” (in small letters) is to be considered independently from “X” (in capital letters) used for the first time in SEQ ID NO: 416 of the present invention. 
     SEQ ID NO: 6 comprises SEQ ID NO: 1. 
     The most advantageous immunosuppressive domains of the wild type ENV proteins according to the invention comprise the following sequences: 
     HIV-1 ENV protein comprises the amino acid sequence AVERYLKDQ (SEQ ID NO: 7), 
     HIV-2 ENV protein comprises the amino acid sequence AIEKYLKDQ (SEQ ID NO: 8), and 
     SIV ENV protein comprises the amino acid sequence SEQ ID NO: 7 or 8. 
     When applying the mutations as defined above, the ISU domain looses its immunosuppressive properties. 
     In said SEQ ID NO: 6, the underlined amino acids are the essential amino acids. 
     In the invention, the ISU domain, as defined by SEQ ID NO: 6, is the minimal essential domain of the ENV protein according to the invention which harbours an immunosuppressive activity. 
     
       
         
               
             
               
               
             
               
             
               
               
             
               
             
               
               
             
           
               
                   
               
               
                 Examples of wild type ISU domains: 
               
               
                   
               
             
             
               
                 HIV-1 
               
             
          
           
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQA 
                 (SEQ ID NO: 366) 
               
               
                 RILAVERYLKDQQLLG 
               
               
                   
               
               
                 SGIVQQQNNLLRAIEAQQHLLKLTVWGIKQLQA 
                 (SEQ ID NO: 367) 
               
               
                 RILAVERYLKDQQLLG 
               
               
                   
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQA 
                 (SEQ ID NO: 368) 
               
               
                 RVLAVERYLKDQQLLG 
               
               
                   
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQA 
                 (SEQ ID NO: 369) 
               
               
                 RILAVERYLKDQQLLG 
               
               
                   
               
               
                 SGIVQQQNNLLRAIEAQQQMLQLTVWGIKQLRA 
                 (SEQ ID NO: 370) 
               
               
                 RVLAVERYLRDQQLLG 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQA 
                 (SEQ ID NO: 371) 
               
               
                 RVLAVERYLRDQQLLG 
               
               
                   
               
             
          
           
               
                 SIV 
               
             
          
           
               
                 SGIVQQQNNLLKAIEAQQHLLQLSIWGVKQLQA 
                 (SEQ ID NO: 372) 
               
               
                 RLLAVERYLQDQQILG 
               
               
                   
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLSVWGIKQLQA 
                 (SEQ ID NO: 373) 
               
               
                 RVLAIERYLRDQQILG 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQT 
                 (SEQ ID NO: 374) 
               
               
                 RVSAIEKYLKDQAQLN 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQT 
                 (SEQ ID NO: 375) 
               
               
                 RVTAIEKYLKDQAQLN 
               
               
                   
               
             
          
           
               
                 HIV2 
               
             
          
           
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQA 
                 (SEQ ID NO: 376) 
               
               
                 RVTAIEKYLKDQAQLN 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQT 
                 (SEQ ID NO: 377) 
               
               
                 RVTAIEKYLKDQALLN 
               
               
                   
               
             
          
         
       
     
     The localization of an ISU domain can be determined in all ENV proteins of viruses as described in Benit et al. 2001 , Journal of Virology , Vol. 75, No. 23, p. 11709-11719. In a broad meaning, the ISU domain is defined by its structure and its localization, irrespective of the fact that it possesses or not an immunosuppressive activity. 
     In the invention, the ISU domain refers to a specific domain in which a mutation can affect the immunosuppressive property of the ENV protein. 
     The immunosuppressive property of the ENV protein is preferably measured using in vivo procedures, which are representative of the physiological environment. 
     The immunosuppressive properties of the mutated ENV proteins according to the invention are measured according to an in vivo procedure to assay the immunosuppressive activity of a ENV protein disclosed previously [Mangeney and Heidmann  Proc Natl Acad Sci USA  1998; 95: 14920-14925; Mangeney et al.  Proc Natl Acad Sci USA,  2007, 104(51):20534-9]. 
     As a physiological test, this in vivo procedure is performed using ENV proteins, or fragment thereof, which are not associated to another component or carrier proteins, such as BSA. 
     Briefly, a wild-type (wild type lentiviral ENV protein) or modified nucleic acid expressing the protein to be tested (mutated lentiviral ENV protein) is transfected in tumour cell lines such as MCA 205 or C18.1 cell lines by known transfection methods. The tumour cells expressing the protein to be tested are then injected especially subcutaneous (s.c.) injection to a host, generally mice. Following said injection, the establishment of tumour or, to the contrary, its rejection, is determined and the tumour area is measured. Tumor establishment was determined by palpation and tumor area (mm 2 ) was determined by measuring perpendicular tumor diameters. Immunosuppression index is defined as i=(S env -S none )/S none , wherein S env  is the maximum area reached by a tumour expressing an envelope protein and S none  is the maximum area reached by a tumour not expressing ENV protein (negative control). 
     According to an embodiment of the invention, the above defined ratio relative to the immunosuppressive index can be less than 0.2, and can even have a negative value (see  FIGS. 2 and 3 ). 
     In vitro assay could be carried out, using high doses of synthetic peptides but they are indirect and less convincing, since the expression “immunosuppressive” is relevant when applied to animals possessing a complete immune system and not to cell lines. 
     An additional difficulty for the functional characterization of an ISU domain relies on the fact that the ISU carried by the retroviral ENV proteins is a highly structured proteic domain, with trimer formation within the complete ENV proteins (Caffrey M.,  Biochimica et Biophysica Acta,  1536:116-122, 2001; Caffrey et al.,  The EMBO Journal , Vol. 17, No. 16, p. 4572-4584, 1998). Such structures are not naturally formed with ISU peptides of limited length, and this is most probably why most studies carried out with peptides provide irrelevant results and/or are dependent on specific coupling of the peptides to carrier proteins (such as BSA, e.g. Denner et al.,  Current Science, AIDS  1994, 8:1063-1072). 
     As mentioned above, the ENV proteins according to the invention are mutated. This mutation is made in vitro. Thus, the mutated ENV proteins according to the invention are isolated, and does not correspond to naturally occurring counterpart. 
     As mentioned above, the lentiviral mutated ENV proteins are substantially devoid of immunosuppressive properties. This means that the mutated ENV proteins according to the invention have no, or have reduced immunosuppressive properties with respect to the natural non mutated ENV protein from a virus of the same species. For instance, a mutated HIV ENV protein according to the invention has reduced immunosuppressive properties with respect to the wild type HIV ENV protein. 
     In the invention, the terms “substantially devoid of immunosuppressive properties” means that the mutated ENV proteins according to the invention have an immunosuppressive index less than about 0.2 [Mangeney and Heidmann  Proc Natl Acad Sci USA  1998; 95: 14920-14925; Mangeney et al.  Proc Natl Acad Sci USA,  2007, 104(51):20534-9]. 
     In the invention, structures responsible for the antigenicity of the mutated lentiviral ENV protein are essentially preserved. 
     As intended herein, the expression “structures responsible for antigenicity” relates to structures of the protein which are liable to interact with components of the immune system such as antibodies or membrane receptors of immune cells, in particular T cells. 
     The mutation(s) within the immunosuppressive domain of the lentiviral ENV proteins is (are) sufficient to decrease the immunosuppressive activity of the mutated lentiviral ENV protein with respect to the corresponding wild type ENV. However, it might be advantageous that another amino acid be also mutated because it ensures that the structure of the mutated ENV protein is essentially conserved with respect to the corresponding wild type ENV protein. 
     The mutated lentiviral ENV protein has substantially retained the structure, especially the antigenic structure, e.g., immunogenic determinants, of the original determined lentiviral ENV protein, i.e. the wild type non mutated lentiviral ENV protein. 
     These properties can be evaluated by measuring the fusion and/or infectious properties of said mutated lentiviral ENV with respect to the same properties in the wild type non mutated lentiviral ENV protein (see example). 
     Generally speaking, the mutated ENV protein involved in the present invention has an average length of about 700 to about 950 amino acids. 
     The invention encompasses fragments of the mutated ENV protein as defined above, provided that said fragment:
         comprises at least the sequence SEQ ID NO: 2, as defined above,   comprises at least 40 amino acids, preferably comprises at least 50 amino acids,   is substantially devoid of immunosuppressive properties, as defined above,   preferably, comprises the extracellular parts of the ENV protein,   retains the structure of the ENV protein from which it derives,   harbours the same epitopes as the corresponding fragment in the wild type ENV protein.       

     According to a particular embodiment, the fragment of the mutated ENV protein of the invention can comprise about 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650 or 700 amino acids. These values are given only in an illustrative way, as the man skilled in the art will understand that the fragment can comprise any number of amino acids comprised between 40 and 700. 
     Advantageously, the fragments according to the invention are such that, while retaining the antigenic structure of the full length mutated ENV protein, and thus of the wild type ENV protein, they have lost major antigenic regions that are responsible for antigenicity in another region than the region corresponding to the immunosuppressive domain. 
     The invention also relates to a pharmaceutical composition comprising as active substance: 
     a) an isolated non naturally occurring mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein, said mutated human or simian lentiviral ENV protein having at least 70% identity, preferably at least 80% identity, to one sequence chosen from the group consisting of SEQ ID NO: 216, SEQ ID NO: 420 and SEQ ID NO: 421,
 
said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:
 
                                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein,
 
X represents any amino acid,
 
     and either 
     X a  is A, F, G, L, R or deleted, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or 
     X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G, R or deleted, or 
     X a  is A, F, G, L, R or deleted, and X b  is A, F, G, R or deleted, 
     
         
         
           
             or
 
b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,
 
said fragment comprising at least 40 amino acids,
 
said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:
 
           
         
       
    
                                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein,
 
X represents any amino acid,
 
     and either 
     X a  is A, F, G, L, R or deleted, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or 
     X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G, R or deleted, or 
     X a  is A, F, G, L, R or deleted, and X b  is A, F, G, R or deleted, 
     in association with a pharmaceutically acceptable carrier, 
     said substantial absence of immunosuppressive activity of the above mentioned mutated human or simian lentiviral ENV protein or of the above defined fragment being liable to be assessed by the fact that in an in vivo assay involving engrafted tumor cells rejection, said tumor cells being transduced either so as to express said mutated ENV protein or said fragment (“mutated ENV tumor cells”),
 
or said tumor cells being transduced so as to express said wild type ENV protein or a fragment thereof (“wild type ENV tumor cells”),
 
or said tumor cells being not transduced (“normal tumor cells”), the following ratio:
 
immunosuppression index of said mutated ENV protein or of said fragment (i mutated env )/immunosuppression index of wild type ENV protein (i wild type env ) is less than 0.5, i mutated env  being defined by: (maximum area reached by mutated ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells), and
 
i wild type env  being defined by: (maximum area reached by wild type ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells).
 
     In a particular embodiment, the invention relates to a pharmaceutical composition as defined above comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, F, G, L or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G or R, or 
             X a  is A, F, G, L or R, and X b  is A, F, G or R, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence: 
           
         
       
    
     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, F, G, L or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G or R, or 
             X a  is A, F, G, L or R, and X b  is A, F, G or R, 
             in association with a pharmaceutically acceptable carrier. 
           
         
       
    
     The invention relates to a pharmaceutical composition as defined above comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein 
             X represents any amino acid,
           and either   
         
             X a  is A, F, G, L or R, and X b  is L, I, V, M or P, or 
             X a  is Y, I, H, C or T, and X b  is A, F, G or R, or 
             X a  is A, F, G, L or R, and X b  is A, F, G or R, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence: 
           
         
       
    
     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein 
             X represents any amino acid,
           and either   
         
             X a  is A, F, G, L or R, and X b  is L, I, V, M or P, or 
             X a  is Y, I, H, C or T, and X b  is A, F, G or R, or 
             X a  is A, F, G, L or R, and X b  is A, F, G or R, 
             in association with a pharmaceutically acceptable carrier. 
           
         
       
    
     According to a particular embodiment, the invention relates to a pharmaceutical composition as defined above comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is F, G or R, 
             or 
             X a  is F or L, and X b  is F, G or R, 
             or 
             X a  is A, G or R, and X b  is A, 
             or 
             X a  is A, G or R, and X b  is F, G or R, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence: 
           
         
       
    
     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, 
             or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is F, G or R, 
             or 
             X a  is F or L, and X b  is F, G or R, 
             or 
             X a  is A, G or R, and X b  is A, 
             or 
             X a  is A, G or R, and X b  is F, G, R,
 
in association with a pharmaceutically acceptable carrier.
 
           
         
       
    
     According to a particular embodiment, the invention relates to a pharmaceutical composition as defined above comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is L, I, V, M or P, 
             or 
             X a  is Y, I, H, C or T, and X b  is F, G or R, 
             or 
             X a  is F or L, and X b  is F, G or R, 
             or 
             X a  is A, G or R, and X b  is A, 
             or 
             X a  is A, G or R, and X b  is F, G or R, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence: 
           
         
       
    
     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is L, I, V, M or P, 
             or 
             X a  is Y, I, H, C or T, and X b  is F, G or R, 
             or 
             X a  is F or L, and X b  is F, G or R, 
             or 
             X a  is A, G or R, and X b  is A, 
             or 
             X a  is A, G or R, and X b  is F, G or R, 
             in association with a pharmaceutically acceptable carrier. 
           
         
       
    
     According to another particular embodiment, the invention also relates to a pharmaceutical composition as defined above comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, 
             or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is F, G or R, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence: 
           
         
       
    
     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, 
             or 
             X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is F, G or R, 
             in association with a pharmaceutically acceptable carrier. 
           
         
       
    
     According to another particular embodiment, the invention relates to a pharmaceutical composition as defined above, comprising as active substance:
         a) an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,   said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of a wild type human or simian lentiviral ENV protein,   said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:       

     
       
         
               
               
               
             
           
               
                   
                 A-[I/V]-E-[K/R]-X a -X b -X-D-Q, 
                 (SEQ ID NO: 416) 
               
             
          
         
       
         
         
           
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is L, I, V, M or P, 
             or 
             X a  is Y, I, H, C or T, and X b  is F, G or R, 
             or 
             b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
             said fragment comprising at least 40 amino acids, 
             said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:
           A-[I/V]-E-[K/R]-X a -X b -X-D-Q (SEQ ID NO: 416),   
         
             wherein, 
             X represents any amino acid,
           and either   
         
             X a  is A, G, or R, and X b  is L, I, V, M or P, 
             or 
             X a  is Y, I, H, C or T, and X b  is F, G or R, 
             in association with a pharmaceutically acceptable carrier. 
           
         
       
    
     According to another particular embodiment, the invention relates to a pharmaceutical composition as defined above,
         wherein
           X a  is R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or   X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is R, or   X a  is R, and X b  is R.   
               

     According to another particular embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said isolated mutated human or simian lentiviral ENV protein or said fragment of said isolated mutated human or simian lentiviral ENV protein comprises one of the following amino acid sequences: 
     
       
         
               
               
               
             
           
               
                   
                 A-I-E-K-X a -X b -X-DQ, 
                 (SEQ ID NO: 422) 
               
               
                   
                   
               
               
                   
                 A-I-E-R-X a -X b -X-DQ, 
                 (SEQ ID NO: 423) 
               
               
                   
                   
               
               
                   
                 A-V-E-K-X a -X b -X-DQ, 
                 (SEQ ID NO: 424) 
               
               
                   
                   
               
               
                   
                 A-V-E-R-X a -X b -X-DQ. 
                 (SEQ ID NO: 425) 
               
             
          
         
       
     
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein the resulting immunosuppressive domain, contained in the mutated lentiviral protein, comprises the amino acid sequence of the list consisting of: SEQ ID NO:9 to SEQ ID NO:37. 
     In the invention “SEQ ID NO: 9 to SEQ ID NO:37” encompass SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36 and SEQ ID NO: 37. 
     The correspondence is the following one: 
     
       
         
               
               
               
             
           
               
                   
                 AVERALKD 
                 SEQ ID NO: 9 
               
               
                   
                   
               
               
                   
                 AVERFLKD 
                 SEQ ID NO: 10 
               
               
                   
                   
               
               
                   
                 AVERGLKD 
                 SEQ ID NO: 11 
               
               
                   
                   
               
               
                   
                 AVERLLKD 
                 SEQ ID NO: 12 
               
               
                   
                   
               
               
                   
                 AVERRLKD 
                 SEQ ID NO: 13 
               
               
                   
                   
               
               
                   
                 AVERYAKD 
                 SEQ ID NO: 14 
               
               
                   
                   
               
               
                   
                 AVERYFKD 
                 SEQ ID NO: 15 
               
               
                   
                   
               
               
                   
                 AVERYGKD 
                 SEQ ID NO: 16 
               
               
                   
                   
               
               
                   
                 AVERYRKD 
                 SEQ ID NO: 17 
               
               
                   
                   
               
               
                   
                 AVERAAKD 
                 SEQ ID NO: 18 
               
               
                   
                   
               
               
                   
                 AVERAFKD 
                 SEQ ID NO: 19 
               
               
                   
                   
               
               
                   
                 AVERAGKD 
                 SEQ ID NO: 20 
               
               
                   
                   
               
               
                   
                 AVERARKD 
                 SEQ ID NO: 21 
               
               
                   
                   
               
               
                   
                 AVERFAKD 
                 SEQ ID NO: 22 
               
               
                   
                   
               
               
                   
                 AVERFFKD 
                 SEQ ID NO: 23 
               
               
                   
                   
               
               
                   
                 AVERFGKD 
                 SEQ ID NO: 24 
               
               
                   
                   
               
               
                   
                 AVERFRKD 
                 SEQ ID NO: 25 
               
               
                   
                   
               
               
                   
                 AVERGAKD 
                 SEQ ID NO: 26 
               
               
                   
                   
               
               
                   
                 AVERGFKD 
                 SEQ ID NO: 27 
               
               
                   
                   
               
               
                   
                 AVERGGKD 
                 SEQ ID NO: 28 
               
               
                   
                   
               
               
                   
                 AVERGRKD 
                 SEQ ID NO: 29 
               
               
                   
                   
               
               
                   
                 AVERLAKD 
                 SEQ ID NO: 30 
               
               
                   
                   
               
               
                   
                 AVERLFKD 
                 SEQ ID NO: 31 
               
               
                   
                   
               
               
                   
                 AVERLGKD 
                 SEQ ID NO: 32 
               
               
                   
                   
               
               
                   
                 AVERLRKD 
                 SEQ ID NO: 33 
               
               
                   
                   
               
               
                   
                 AVERRAKD 
                 SEQ ID NO: 34 
               
               
                   
                   
               
               
                   
                 AVERRFKD 
                 SEQ ID NO: 35 
               
               
                   
                   
               
               
                   
                 AVERRGKD 
                 SEQ ID NO: 36 
               
               
                   
                   
               
               
                   
                 AVERRRKD 
                 SEQ ID NO: 37 
               
             
          
         
       
     
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein the resulting immunosuppressive domain, contained in the mutated lentiviral protein, comprises the amino acid sequence of the list consisting of: SEQ ID NO: 38 to SEQ ID NO: 66. In the invention “SEQ ID NO: 38 to SEQ ID NO: 66” encompass SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65 and SEQ ID NO: 66. 
     The correspondence is the following one: 
     
       
         
               
               
               
             
           
               
                   
                 AIEKALKD 
                 SEQ ID NO: 38 
               
               
                   
               
               
                   
                 AIEKFLKD 
                 SEQ ID NO: 39 
               
               
                   
               
               
                   
                 AIEKGLKD 
                 SEQ ID NO: 40 
               
               
                   
               
               
                   
                 AIEKLLKD 
                 SEQ ID NO: 41 
               
               
                   
               
               
                   
                 AIEKRLKD 
                 SEQ ID NO: 42 
               
               
                   
               
               
                   
                 AIEKYAKD 
                 SEQ ID NO: 43 
               
               
                   
               
               
                   
                 AIEKYFKD 
                 SEQ ID NO: 44 
               
               
                   
               
               
                   
                 AIEKYGKD 
                 SEQ ID NO: 45 
               
               
                   
               
               
                   
                 AIEKYRKD 
                 SEQ ID NO: 46 
               
               
                   
               
               
                   
                 AIEKAAKD 
                 SEQ ID NO: 47 
               
               
                   
               
               
                   
                 AIEKAFKD 
                 SEQ ID NO: 48 
               
               
                   
               
               
                   
                 AIEKAGKD 
                 SEQ ID NO: 49 
               
               
                   
               
               
                   
                 AIEKARKD 
                 SEQ ID NO: 50 
               
               
                   
               
               
                   
                 AIEKFAKD 
                 SEQ ID NO: 51 
               
               
                   
               
               
                   
                 AIEKFFKD 
                 SEQ ID NO: 52 
               
               
                   
               
               
                   
                 AIEKFGKD 
                 SEQ ID NO: 53 
               
               
                   
               
               
                   
                 AIEKFRKD 
                 SEQ ID NO: 54 
               
               
                   
               
               
                   
                 AIEKGAKD 
                 SEQ ID NO: 55 
               
               
                   
               
               
                   
                 AIEKGFKD 
                 SEQ ID NO: 56 
               
               
                   
               
               
                   
                 AIEKGGKD 
                 SEQ ID NO: 57 
               
               
                   
               
               
                   
                 AIEKGRKD 
                 SEQ ID NO: 58 
               
               
                   
               
               
                   
                 AIEKLAKD 
                 SEQ ID NO: 59 
               
               
                   
               
               
                   
                 AIEKLFKD 
                 SEQ ID NO: 60 
               
               
                   
               
               
                   
                 AIEKLGKD 
                 SEQ ID NO: 61 
               
               
                   
               
               
                   
                 AIEKLRKD 
                 SEQ ID NO: 62 
               
               
                   
               
               
                   
                 AIEKRAKD 
                 SEQ ID NO: 63 
               
               
                   
               
               
                   
                 AIEKRFKD 
                 SEQ ID NO: 64 
               
               
                   
               
               
                   
                 AIEKRGKD 
                 SEQ ID NO: 65 
               
               
                   
               
               
                   
                 AIEKRRKD 
                 SEQ ID NO: 66 
               
             
          
         
       
     
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein the resulting immunosuppressive domain, contained in the mutated lentiviral protein, comprises the amino acid sequence of the list consisting of: SEQ ID NO: 67 to SEQ ID NO: 95. 
     In the invention “SEQ ID NO: 67 to SEQ ID NO:95” encompass SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94 and SEQ ID NO: 95. 
     The correspondence is the following one: 
     
       
         
               
               
               
             
           
               
                   
                 AIERALKD 
                 SEQ ID NO: 67 
               
               
                   
               
               
                   
                 AIERFLKD 
                 SEQ ID NO: 68 
               
               
                   
               
               
                   
                 AIERGLKD 
                 SEQ ID NO: 69 
               
               
                   
               
               
                   
                 AIERLLKD 
                 SEQ ID NO: 70 
               
               
                   
               
               
                   
                 AIERRLKD 
                 SEQ ID NO: 71 
               
               
                   
               
               
                   
                 AIERYAKD 
                 SEQ ID NO: 72 
               
               
                   
               
               
                   
                 AIERYFKD 
                 SEQ ID NO: 73 
               
               
                   
               
               
                   
                 AIERYGKD 
                 SEQ ID NO: 74 
               
               
                   
               
               
                   
                 AIERYRKD 
                 SEQ ID NO: 75 
               
               
                   
               
               
                   
                 AIERAAKD 
                 SEQ ID NO: 76 
               
               
                   
               
               
                   
                 AIERAFKD 
                 SEQ ID NO: 77 
               
               
                   
               
               
                   
                 AIERAGKD 
                 SEQ ID NO: 78 
               
               
                   
               
               
                   
                 AIERARKD 
                 SEQ ID NO: 79 
               
               
                   
               
               
                   
                 AIERFAKD 
                 SEQ ID NO: 80 
               
               
                   
               
               
                   
                 AIERFFKD 
                 SEQ ID NO: 81 
               
               
                   
               
               
                   
                 AIERFGKD 
                 SEQ ID NO: 82 
               
               
                   
               
               
                   
                 AIERFRKD 
                 SEQ ID NO: 83 
               
               
                   
               
               
                   
                 AIERGAKD 
                 SEQ ID NO: 84 
               
               
                   
               
               
                   
                 AIERGFKD 
                 SEQ ID NO: 85 
               
               
                   
               
               
                   
                 AIERGGKD 
                 SEQ ID NO: 86 
               
               
                   
               
               
                   
                 AIERGRKD 
                 SEQ ID NO: 87 
               
               
                   
               
               
                   
                 AIERLAKD 
                 SEQ ID NO: 88 
               
               
                   
               
               
                   
                 AIERLFKD 
                 SEQ ID NO: 89 
               
               
                   
               
               
                   
                 AIERLGKD 
                 SEQ ID NO: 90 
               
               
                   
               
               
                   
                 AIERLRKD 
                 SEQ ID NO: 91 
               
               
                   
               
               
                   
                 AIERRAKD 
                 SEQ ID NO: 92 
               
               
                   
               
               
                   
                 AIERRFKD 
                 SEQ ID NO: 93 
               
               
                   
               
               
                   
                 AIERRGKD 
                 SEQ ID NO: 94 
               
               
                   
               
               
                   
                 AIERRRKD 
                 SEQ ID NO: 95 
               
             
          
         
       
     
     As mentioned above, the previous ENV proteins having their ISU comprising the above sequence are devoid of immunosuppressive properties. 
     Thus, in other words, any ENV protein of human or simian lentivirus having in their ISU an amino acid sequence comprising of the sequences SEQ ID NO: 9 to 95, is devoid of immunosuppressive properties. 
     In other words, a simian or human lentiviral ENV protein comprising, within its ISU domain, an amino acid sequence selected from SEQ ID NO: 9 to 95 is devoid of immunosuppressive properties. 
     In particular, the invention relates to a pharmaceutical composition as defined above, wherein said isolated mutated human or simian lentiviral ENV protein or said fragment of said isolated mutated human or simian lentiviral ENV protein comprises one of the amino acid sequences:
         SEQ ID NO: 13, SEQ ID NO: 42, SEQ ID NO: 71,   SEQ ID NO: 9 to 12,   SEQ ID NO: 14 to 41,   SEQ ID NO: 43 to 70, and   SEQ ID NO: 72 to 95.       

     In particular, the invention relates to a pharmaceutical composition as defined above, wherein said isolated mutated human or simian lentiviral ENV protein or said fragment of said isolated mutated human or simian lentiviral ENV protein comprises one of the amino acid sequences:
         SEQ ID NO: 13, SEQ ID NO: 42, SEQ ID NO: 71,   SEQ ID NO: 9, 11, 15 to 21, 23 to 29, 31 to 38, 40, 44 to 50, 52 to 58, 60 to 67, 69, 73 to 79, 81 to 87, 89 to 95.       

     In the invention, the fragments of the mutated ENV proteins according to the invention comprise or consist of the following sequences: SEQ ID NO: 67 to 211. 
     These fragments are also devoid of immunosuppressive properties. 
     However, these fragments retain the structure and the antigenicity of the corresponding immunosuppressive domain that is not mutated, i.e. the wild type immunosuppressive domain. 
     In the invention, the fragments of the mutated ENV proteins according to the invention comprise or consist of the following sequences: SEQ ID NO: 96 to 211. 
     The correspondences are as follows 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERAL 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 96 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERFL 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 97 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERGL 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 98 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERLL 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 99 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERRL 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 100 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERYA 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 101 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERYF 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 102 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERYG 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 103 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERYR 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 104 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERAA 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 105 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERAF 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 106 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERAG 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 107 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERAR 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 108 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERFA 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 109 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERFF 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 110 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERFG 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 111 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERFR 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 112 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERGA 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 113 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERGF 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 114 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERGG 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 115 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERGR 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 116 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERLA 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 117 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERLF 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 118 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERLG 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 119 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERLR 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 120 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERRA 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 121 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERRF 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 122 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERRG 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 123 
               
               
                   
               
               
                 SGIVQQQSNLLRAIQARQHMLQLTVWGIKQLQARVLAVERRR 
                 SEQ ID 
               
               
                 KDQQLLG 
                 NO: 124 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 LKDQAQLNSWGCAFRQ 
                 NO: 125 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 LKDQAQLNSWGCAFRQ 
                 NO: 126 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 LKDQAQLNSWGCAFRQ 
                 NO: 127 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 LKDQAQLNSWGCAFRQ 
                 NO: 128 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 LKDQAQLNSWGCAFRQ 
                 NO: 129 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 AKDQAQLNSWGCAFRQ 
                 NO: 130 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 FKDQAQLNSWGCAFRQ 
                 NO: 131 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 GKDQAQLNSWGCAFRQ 
                 NO: 132 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 RKDQAQLNSWGCAFRQ 
                 NO: 133 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 AKDQAQLNSWGCAFRQ 
                 NO: 134 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 FKDQAQLNSWGCAFRQ 
                 NO: 135 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 GKDQAQLNSWGCAFRQ 
                 NO: 136 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 RKDQAQLNSWGCAFRQ 
                 NO: 137 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 AKDQAQLNSWGCAFRQ 
                 NO: 138 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 FKDQAQLNSWGCAFRQ 
                 NO: 139 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 GKDQAQLNSWGCAFRQ 
                 NO: 140 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 RKDQAQLNSWGCAFRQ 
                 NO: 141 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 AKDQAQLNSWGCAFRQ 
                 NO: 142 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 FKDQAQLNSWGCAFRQ 
                 NO: 143 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 GKDQAQLNSWGCAFRQ 
                 NO: 144 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 RKDQAQLNSWGCAFRQ 
                 NO: 145 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 AKDQAQLNSWGCAFRQ 
                 NO: 146 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 FKDQAQLNSWGCAFRQ 
                 NO: 147 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 GKDQAQLNSWGCAFRQ 
                 NO: 148 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 RKDQAQLNSWGCAFRQ 
                 NO: 149 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 AKDQAQLNSWGCAFRQ 
                 NO: 150 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 FKDQAQLNSWGCAFRQ 
                 NO: 151 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 GKDQAQLNSWGCAFRQ 
                 NO: 152 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 RKDQAQLNSWGCAFRQ 
                 NO: 153 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 LQDQARLNSWGCAFRQ 
                 NO: 154 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 LQDQARLNSWGCAFRQ 
                 NO: 155 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 LQDQARLNSWGCAFRQ 
                 NO: 156 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 LQDQARLNSWGCAFRQ 
                 NO: 157 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 LQDQARLNSWGCAFRQ 
                 NO: 158 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 AQDQARLNSWGCAFRQ 
                 NO: 159 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 FQDQARLNSWGCAFRQ 
                 NO: 160 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 GQDQARLNSWGCAFRQ 
                 NO: 161 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKY 
                 SEQ ID 
               
               
                 RQDQARLNSWGCAFRQ 
                 NO: 162 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 AQDQARLNSWGCAFRQ 
                 NO: 163 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 FQDQARLNSWGCAFRQ 
                 NO: 164 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 GQDQARLNSWGCAFRQ 
                 NO: 165 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKA 
                 SEQ ID 
               
               
                 RQDQARLNSWGCAFRQ 
                 NO: 166 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 AQDQARLNSWGCAFRQ 
                 NO: 167 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 FQDQARLNSWGCAFRQ 
                 NO: 168 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 GQDQARLNSWGCAFRQ 
                 NO: 169 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKF 
                 SEQ ID 
               
               
                 RQDQARLNSWGCAFRQ 
                 NO: 170 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 AQDQARLNSWGCAFRQ 
                 NO: 171 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 FQDQARLNSWGCAFRQ 
                 NO: 172 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 GQDQARLNSWGCAFRQ 
                 NO: 173 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKG 
                 SEQ ID 
               
               
                 RQDQARLNSWGCAFRQ 
                 NO: 174 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 AQDQARLNSWGCAFRQ 
                 NO: 175 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 FQDQARLNSWGCAFRQ 
                 NO: 176 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 GQDQARLNSWGCAFRQ 
                 NO: 177 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKL 
                 SEQ ID 
               
               
                 RQDQARLNSWGCAFRQ 
                 NO: 178 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 AQDQARLNSWGCAFRQ 
                 NO: 179 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 FQDQARLNSWGCAFRQ 
                 NO: 180 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 GQDQARLNSWGCAFRQ 
                 NO: 181 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQARVTAIEKR 
                 SEQ ID 
               
               
                 RQDQARLNSWGCAFRQ 
                 NO: 182 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKA 
                 SEQ ID 
               
               
                 LKDQAQLNAWGCAFRQ 
                 NO: 183 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKF 
                 SEQ ID 
               
               
                 LKDQAQLNAWGCAFRQ 
                 NO: 184 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKG 
                 SEQ ID 
               
               
                 LKDQAQLNAWGCAFRQ 
                 NO: 185 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKL 
                 SEQ ID 
               
               
                 LKDQAQLNAWGCAFRQ 
                 NO: 186 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKR 
                 SEQ ID 
               
               
                 LKDQAQLNAWGCAFRQ 
                 NO: 187 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKY 
                 SEQ ID 
               
               
                 AKDQAQLNAWGCAFRQ 
                 NO: 188 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKY 
                 SEQ ID 
               
               
                 FKDQAQLNAWGCAFRQ 
                 NO: 189 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKY 
                 SEQ ID 
               
               
                 GKDQAQLNAWGCAFRQ 
                 NO: 190 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKY 
                 SEQ ID 
               
               
                 RKDQAQLNAWGCAFRQ 
                 NO: 191 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKA 
                 SEQ ID 
               
               
                 AKDQAQLNAWGCAFRQ 
                 NO: 192 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKA 
                 SEQ ID 
               
               
                 FKDQAQLNAWGCAFRQ 
                 NO: 193 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKA 
                 SEQ ID 
               
               
                 GKDQAQLNAWGCAFRQ 
                 NO: 194 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKA 
                 SEQ ID 
               
               
                 RKDQAQLNAWGCAFRQ 
                 NO: 195 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKF 
                 SEQ ID 
               
               
                 AKDQAQLNAWGCAFRQ 
                 NO: 196 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKF 
                 SEQ ID 
               
               
                 FKDQAQLNAWGCAFRQ 
                 NO: 197 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKF 
                 SEQ ID 
               
               
                 GKDQAQLNAWGCAFRQ 
                 NO: 198 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKF 
                 SEQ ID 
               
               
                 RKDQAQLNAWGCAFRQ 
                 NO: 199 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKG 
                 SEQ ID 
               
               
                 AKDQAQLNAWGCAFRQ 
                 NO: 200 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKG 
                 SEQ ID 
               
               
                 FKDQAQLNAWGCAFRQ 
                 NO: 201 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKG 
                 SEQ ID 
               
               
                 GKDQAQLNAWGCAFRQ 
                 NO: 202 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKG 
                 SEQ ID 
               
               
                 RKDQAQLNAWGCAFRQ 
                 NO: 203 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKL 
                 SEQ ID 
               
               
                 AKDQAQLNAWGCAFRQ 
                 NO: 204 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKL 
                 SEQ ID 
               
               
                 FKDQAQLNAWGCAFRQ 
                 NO: 205 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKL 
                 SEQ ID 
               
               
                 GKDQAQLNAWGCAFRQ 
                 NO: 206 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKL 
                 SEQ ID 
               
               
                 RKDQAQLNAWGCAFRQ 
                 NO: 207 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKR 
                 SEQ ID 
               
               
                 AKDQAQLNAWGCAFRQ 
                 NO: 208 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKR 
                 SEQ ID 
               
               
                 FKDQAQLNAWGCAFRQ 
                 NO: 209 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKR 
                 SEQ ID 
               
               
                 GKDQAQLNAWGCAFRQ 
                 NO: 210 
               
               
                   
               
               
                 AGIVQQQQQLLDVVKRQQELLRLTVWGTKNLQTRVTAIEKR 
                 SEQ ID 
               
               
                 RKDQAQLNAWGCAFRQ 
                 NO: 211 
               
               
                   
               
             
          
         
       
     
     In particular, the invention relates to a pharmaceutical composition as defined above, wherein said isolated mutated human or simian lentiviral ENV protein or said fragment of said isolated mutated human or simian lentiviral ENV protein comprises one of the amino acid sequences: SEQ ID NO: 96, 98, 100, 102 to 108, 110 to 116, 118 to 125, 127, 129, 131 to 137, 139 to 145, 147 to 154, 156, 158, 160 to 166, 168 to 174, 176 to 183, 185, 187, 189 to 195, 197 to 203, 205 to 211. 
     Advantageously, the invention relates to the pharmaceutical composition as defined above, wherein said mutated protein consists of one of the following sequences SEQ ID NO: 212 to 269 
     
       
         
               
             
               
               
             
               
             
               
               
             
           
               
                   
               
             
             
               
                 HIV-1 LAI 
               
             
          
           
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ ID 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 212 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERALKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ ID 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 213 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQS SGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERFLKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ ID 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 214 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERGLKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ ID 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 215 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERLLKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ ID 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 216 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERRLKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 217 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERYAKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 218 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERYFKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 219 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERYGKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 220 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERYRKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 221 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERAAKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 222 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERAFKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 223 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERAGKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 224 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERARKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 225 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERFAKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 226 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERFFKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 227 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERFGKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 228 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERFRKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 229 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERGAKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 230 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERGFKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 231 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERGGKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 232 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERGRKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 233 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERLAKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 234 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERLFKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 235 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERLGKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 236 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERLRKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 237 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERRAKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 238 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERRFKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 239 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERRGKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWVTVY 
                 SEQ 
               
               
                 YGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTDP 
                 ID NO: 
               
               
                 NPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPC 
                 240 
               
               
                 VKLTPLCVSLKCTDLGNATNTNSSNTNSSSGEMMMEKGEIK 
               
               
                 NCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTS 
               
               
                 VITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVS 
               
               
                 TVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIV 
               
               
                 QLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQA 
               
               
                 HCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIV 
               
               
                 THSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTIT 
               
               
                 LPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDG 
               
               
                 GNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSMTLTV 
               
               
                 QARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL 
               
               
                   AVERRRKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQI 
               
               
                 WNNMTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLEL 
               
               
                 DKWASLWNWFNITNWLWYIKIFIMIVGGLVGLRIVFAVLSIV 
               
               
                 NRVRQGYSPLSFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRL 
               
               
                 VNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGW 
               
               
                 EALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIE 
               
               
                 VVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
             
          
           
               
                 HIV-BH10 
               
             
          
           
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ ID 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 241 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERA   
               
               
                   LKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ ID 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 242 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERF   
               
               
                   LKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ ID 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 243 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERG   
               
               
                   LKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ ID 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 244 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERL   
               
               
                   LKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ ID 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 245 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERR   
               
               
                   LKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ ID 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 246 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERY   
               
               
                   AKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 247 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERY   
               
               
                   FKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMT 
               
               
                 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL 
               
               
                 WNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQ 
               
               
                 GYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLA 
               
               
                 LIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYW 
               
               
                 WNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGAY 
               
               
                 RAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 248 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERY   
               
               
                   GKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 249 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERY   
               
               
                   RKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 250 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERA   
               
               
                   AKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 251 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERA   
               
               
                   FKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMT 
               
               
                 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL 
               
               
                 WNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQ 
               
               
                 GYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLA 
               
               
                 LIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYW 
               
               
                 WNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGAY 
               
               
                 RAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 252 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERA   
               
               
                   GKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 253 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERA   
               
               
                   RKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 254 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERF   
               
               
                   AKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 255 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERF   
               
               
                   FKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMT 
               
               
                 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL 
               
               
                 WNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQ 
               
               
                 GYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLA 
               
               
                 LIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYW 
               
               
                 WNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGAY 
               
               
                 RAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 256 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERF   
               
               
                   GKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 257 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERF   
               
               
                   RKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 258 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERG   
               
               
                   AKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 259 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERG   
               
               
                   FKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMT 
               
               
                 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL 
               
               
                 WNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQ 
               
               
                 GYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLA 
               
               
                 LIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYW 
               
               
                 WNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGAY 
               
               
                 RAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 260 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERG   
               
               
                   GKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 261 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERG   
               
               
                   RKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 262 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERL   
               
               
                   AKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 263 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERL   
               
               
                   FKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMT 
               
               
                 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL 
               
               
                 WNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQ 
               
               
                 GYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLA 
               
               
                 LIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYW 
               
               
                 WNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGAY 
               
               
                 RAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 264 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERL   
               
               
                   GKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 265 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERL   
               
               
                   RKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 266 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERR   
               
               
                   AKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 267 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERR   
               
               
                   FKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNMT 
               
               
                 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASL 
               
               
                 WNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQ 
               
               
                 GYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLA 
               
               
                 LIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYW 
               
               
                 WNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQGAY 
               
               
                 RAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 268 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERR   
               
               
                   GKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTV 
                 SEQ 
               
               
                 YYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHACVPTD 
                 ID NO: 
               
               
                 PNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKP 
                 269 
               
               
                 CVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNI 
               
               
                 STSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQAC 
               
               
                 PKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCT 
               
               
                 HGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKTIIVQLNQS 
               
               
                 VEINCTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHCNIS 
               
               
                 RAKWNNTLKQIDSKLREQFGNNKTIIFKQSSGGDPEIVTHSFN 
               
               
                 CGGEFFYCNSTQLFNSTWFNSTWSTKGSNNTEGSDTITLPCRI 
               
               
                 KQIINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNSN 
               
               
                 NESEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKR 
               
               
                 RVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQL 
               
               
                 LSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARIL AVERR   
               
               
                   RKDQ QLLGIWGCSGKLICTTAVPWNASWSNKSLEQIWNNM 
               
               
                 TWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWAS 
               
               
                 LWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVR 
               
               
                 QGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSL 
               
               
                 ALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKY 
               
               
                 WWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQG 
               
               
                 AYRAIRHIPRRIRQGLERILL 
               
               
                   
               
             
          
         
       
     
     The invention also encompasses the variants of the above sequences, harbouring the above mentioned mutations, and conferring to said variant a lack of immunosuppressive properties. 
     In particular, the invention relates to a pharmaceutical composition as defined above, wherein said isolated mutated human or simian lentiviral ENV protein consists of one of the amino acid sequences: SEQ ID NO: 212, 214, 216, 218 to 224, 226 to 232, 234 to 241, 243, 245, 247 to 253, 255 to 261, 263 to 269. 
     The invention also relates to a pharmaceutical composition as defined above, wherein said mutated protein comprises additional mutations either downstream the C-terminal end of the sequence SEQ ID NO: 416 or upstream the N-terminal end of SEQ ID NO: 416. 
     These additional mutations can be advantageous to maintain the three-dimensional structure of the immunosuppressive domain and of the ENV protein (see details concerning the membrane expression of the ENV protein [see  FIG. 4  and example] and concerning infectivity [see  FIG. 5  and example]). 
     In a particular embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said mutated protein comprises an additional mutation in one at least of the amino acids at positions 29, 36 and 37 of SEQ ID NO: 426: 
                               (SEQ ID NO: 426)                A[I/V]E[K/R]X a X b X 1 DQX 2 X 3 LX 4 X 5 WGC           [A/S][F/G]X 6 X 7 CVX 8 TX 9 VPX c X 10 Z 1 Z 2 Z 3 Z 4 Z 5 X d X e [S/T]            
wherein
         X a  and X b  are as defined above,   X 1  to X 10  represent any amino acid,   Z 1  to Z 5  represent no amino acid or any amino acid, independently from each other such that
           X c  is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, Y, or deleted, preferably A, D, or N,   X d  is A, C, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, Y, W, or deleted, preferably A, G, S or Y,   X e  is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, Y, W, or deleted, preferably A, D or N.   
               

     This sequence contains the following amino acid sequence A[I/V]E[K/R]X a X b X 1 DQ (SEQ ID NO: 416) elongated on its C-terminal end in which additional mutations are present. It is to be noted that “X 1 ” in the above mentioned sequence SEQ ID NO: 426 has the same meaning as “X” in SEQ ID NO: 416. 
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, said mutated protein comprising the amino acid sequences of the group consisting of SEQ ID NO: 271 to SEQ ID NO: 283. 
     
       
         
               
             
           
               
                 SEQ ID NO: 271, contains the mutations Y41R, K72A: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSN   A   SLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 272, contains the mutations Y41R, K72G: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSN   G   SLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 273, contains the mutations Y41R, K72S: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSN   S   SLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 274, contains the mutations Y41R, W65D: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVP   D   NASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 275, contains the mutations Y41R, W65A: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVP   A   NASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 276, contains the mutations Y41R, W65N: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVP   N   NASWSNKSLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 277, contains the mutations Y41R, S73D: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSNK   D   LEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 278, contains the mutations Y41R, S73A: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSNK   A   LEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 279, contains the mutations Y41R, S73N: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSNK   N   LEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 280, contains the mutations Y41R, K72Y: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSN   Y   SLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 281, contains the mutations R40A, 
               
               
                 Y41R, K72A: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVE   AR   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSN   A   SLEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 282, contains the mutations Y41R, 
               
               
                 K72A, S73A: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVPWNASWSN   AA   LEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
               
                   
               
               
                 SEQ ID NO: 283, contains the mutations Y41R, 
               
               
                 W65A, K72A, S73A: 
               
               
                 SGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVER   R   LKDQQLLGI 
               
               
                 WGCSGKLICTTAVP   A   NASWSN   AA   LEQIWNNMTWMEWDREINNYTSLIHSL 
               
               
                 IEESQNQQEKNEQEL. 
               
             
          
         
       
     
     The mutations in the above mutated peptides are indicated by the amino acid residues which are bolded and underlined. 
     In another aspect, the invention relates to a pharmaceutical composition as defined above, comprising an additional mutation of one at least of the amino acids X 11 , X 12 , X 13  and X 14  in the following sequence (containing the above defined SEQ ID NO: 416 sequence): 
                               (SEQ ID NO: 428)                X 11 X 12 X 13 X 14 ILA[I/V]E[K/R]X a X b X 1 DQ,            
wherein
 
X 1  represents any amino acid,
 
X a  and X b  are as defined above,
 
X 11  is:
         either deleted,   or A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, Y or W, in particular A, G or R, and/or
 
X 12  is:
   either deleted,   or A, C, D, E, F, G, H, I, K, L, M, N, P, R, S, T, V, Y or W, in particular A, G or R,
 
and/or
 
X 13  is:
   either deleted,   or C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, Y or W, in particular R or G,
 
and/or
 
X 14  is:
   either deleted,   or A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, V, Y or W, in particular A or G.       

     This sequence contains the following amino acid sequence A[I/V]E[K/R]X a X b X 1 DQ (SEQ ID NO: 416) elongated on its N-terminal end in which additional mutations are present. 
     It is to be noted that “X 1 ” in SEQ ID NO: 428 has exactly the same meaning as “X” in SEQ ID NO: 416. 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said mutated lentiviral protein, said variant or said fragment harbour a three-dimensional structure similar to the structure of the natural non mutated lentiviral ENV protein, non mutated lentiviral ENV variant or non mutated lentiviral ENV fragment thereof. 
     The skilled person knows how to measure the antigenicity, by using standard proceedings. 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said mutated lentiviral protein, said variant or said fragment are expressed at the plasma membrane at a level substantially identical to the expression at the plasma membrane of the natural non mutated lentiviral ENV protein, non mutated lentiviral ENV variant or non mutated lentiviral ENV fragment thereof. 
     The membrane expression of the lentiviral ENV protein according to the invention can be measured by any techniques allowing determination of a plasma membrane protein. For instance, cells can be transfected with an expression vector allowing the expression of the mutated lentiviral ENV protein according to the invention. Cells are then incubated with an antibody recognizing specifically the extracellular part of said lentiviral mutated ENV protein. The complex (antibody/ENV protein) is detected by another antibody, and the complex can be quantified by flow cytometry (see for instance  FIG. 4 , and example). 
     If no complex is detected, the mutated ENV protein is not expressed at the plasma membrane. On the contrary, if the protein is expressed, this means that the mutated ENV protein is expressed at the plasma membrane. 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said mutated lentiviral ENV protein is such that a lentivirus, or a pseudotype, expressing said mutated lentiviral ENV protein, instead of the non mutated ENV protein, has a viral titer similar to the viral titer of said lentivirus, or pseudotype, expressing the non mutated lentiviral protein. 
     Viral titer is measured according to a commonly used protocol, and as described in the example (see  FIG. 5 ). 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said mutated lentiviral ENV protein is a HIV-1 lentiviral protein consisting of the amino acid sequences SEQ ID NO: 284 to SEQ ID NO: 292. 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 SEQ ID NO: 284 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41R 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERRLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 285 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41R, K72A 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERRLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNASLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 286 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41R, K72G 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERRLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNGSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 287 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41R, K72S 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERRLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNSSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 288 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41G 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERGLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 289 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41L 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERLLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 290 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41A 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERALKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 291 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 Y41F 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERFLKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
               
                 SEQ ID NO: 292 
                 MRVKEKYQHLWRWGWKWGTMLLGILMICSATEKLWV 
               
               
                 L42R 
                 TVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATH 
               
               
                   
                 ACVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDI 
               
               
                   
                 ISLWDQSLKPCVKLTPLCVSLKCTDLGNATNTNSSN 
               
               
                   
                 TNSSSGEMMMEKGEIKNCSFNISTSIRGKVQKEYAF 
               
               
                   
                 FYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFE 
               
               
                   
                 PIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQC 
               
               
                   
                 THGIRPVVSTQLLLNGSLAEEEVVIRSANFTDNAKT 
               
               
                   
                 IIVQLNQSVEINCTRPNNNTRKSIRIQRGPGRAFVT 
               
               
                   
                 IGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGN 
               
               
                   
                 NKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLF 
               
               
                   
                 NSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMW 
               
               
                   
                 QEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNN 
               
               
                   
                 GSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPT 
               
               
                   
                 KAKRRVVQREKRAVGIGALFLGFLGAAGSTMGARSM 
               
               
                   
                 TLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVW 
               
               
                   
                 GIKQLQARIL AVERYRKDQ QLLGIWGCSGKLICTTA 
               
               
                   
                 VPWNASWSNKSLEQIWNNMTWMEWDREINNYTSLIH 
               
               
                   
                 SLIEESQNQQEKNEQELLELDKWASLWNWFNITNWL 
               
               
                   
                 WYIKIFIMIVGGLVGLRIVFAVLSIVNRVRQGYSPL 
               
               
                   
                 SFQTHLPTPRGPDRPEGIEEEGGERDRDRSIRLVNG 
               
               
                   
                 SLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGR 
               
               
                   
                 RGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVA 
               
               
                   
                 EGTDRVIEVVQGACRAIRHIPRRIRQGLERILL 
               
               
                   
               
             
          
         
       
     
     Also, the following proteins are advantageous in the invention: 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 SEQ ID NO: 293 
                 MGCLGNQLLIAILLLSVYGIYCTQYVTVFYGVPAWR 
               
               
                 SIV MM251 
                 NATIPLFCATKNRDTWGTTQCLPDNGDYSELALNVT 
               
               
                 L42R 
                 ESFDAWENTVTEQAIEDVWQLFETSIKPCVKLSPLC 
               
               
                   
                 ITMRCNKSETDRWGLTKSSTTITTAAPTSAPVSEKI 
               
               
                   
                 DMVNETSSCIAQNNCTGLEQEQMISCKFTMTGLKRD 
               
               
                   
                 KTKEYNETWYSTDLVCEQGNSTDNESRCYMNHCNTS 
               
               
                   
                 VIQESCDKHYWDTIRFRYCAPPGYALLRCNDTNYSG 
               
               
                   
                 FMPKCSKVVVSSCTRMMETQTSTWFGFNGTRAENRT 
               
               
                   
                 YIYWHGRDNRTIISLNKYYNLTMKCRRPGNKTVLPV 
               
               
                   
                 TIMSGLVFHSQPINDRPKQAWCWFGGKWKDAIKEVK 
               
               
                   
                 QTIVKHPRYTGTNNTDKINLTAPGGGDPEVTFMWTN 
               
               
                   
                 CRGEFLYCKMNWFLNWVEDRDVTTQRPKERHRRNYV 
               
               
                   
                 PCHIRQIINTWHKVGKNVYLPPREGDLTCNSTVTSL 
               
               
                   
                 IANIDWTDGNQTSITMSAEVAELYRLELGDYKLVEI 
               
               
                   
                 TPIGLAPTDVKRYTTGGTSRNKRGVFVLGFLGFLAT 
               
               
                   
                 AGSAMGAASLTLTAQSRTLLAGIVQQQQQLLDVVKR 
               
               
                   
                 QQELLRLTVWGTKNLQTRVT AIEKYRKDQ AQLNAWG 
               
               
                   
                 CAFRQVCHTTVPWPNASLTPDWNNDTWQEWERKVDF 
               
               
                   
                 LEENITALLEEAQIQQEKNMYELQKLNSWDVFGNWF 
               
               
                   
                 DLASWIKYIQYGIYVVVGVILLRIVIYIVQMLAKLR 
               
               
                   
                 QGYRPVFSSPPSYFQXTHTQQDPALPTREGKEGDGG 
               
               
                   
                 EGGGNSSWPWQIEYIHFLIRQLIRLLTWLFSNCRTL 
               
               
                   
                 LSRAYQILQPILQRLSATLRRVREVLRTELTYLQYG 
               
               
                   
                 WSYFHEAVQAGWRSATETLAGAWRDLWETLRRGGRW 
               
               
                   
                 ILAIPRRIRQGLELTLL 
               
               
                   
               
               
                 SEQ ID NO: 294 
                 MEPGRNQLFVVILLTSACLVYCSQYVTVFYGIPAWK 
               
               
                 HIV2 L42R 
                 NASIPLFCATKNRDTWGTIQCLPDNDDYQEIILNVT 
               
               
                   
                 EAFDAWNNTVTEQAVEDVWHLFETSIKPCVKLTPLC 
               
               
                   
                 VAMNCSRVQGNTTTPNPRTSSSTTSRPPTSAASIIN 
               
               
                   
                 ETSNCIENNTCAGLGYEEMMQCEFNMKGLEQDKKRR 
               
               
                   
                 YKDTWYLEDVVCDNTTAGTCYMRHCNTSIIKESCDK 
               
               
                   
                 HYWDAMRFRYCAPPGFALLRCNDTNYSGFEPKCTKV 
               
               
                   
                 VAASCTRMMETQTSTWFGFNGTRAENRTYIYWHGRD 
               
               
                   
                 NRTIISLNKYYNLTMRCKRPGNKTVLPITLMSGLVF 
               
               
                   
                 HSQPINTRPRQAWCRFGGRWREAMQEVKQTLVQHPR 
               
               
                   
                 YKGINDTGKINFTKPGAGSDPEVAFMWTNCRGEFLY 
               
               
                   
                 CNMTWFLNWVEDKNQTRRNYCHIKQIINTWHKVGKN 
               
               
                   
                 VYLPPREGELACESTVTSIIANIDIDKNRTHTNITF 
               
               
                   
                 SAEVAELYRLELGDYKLIEITPIGFAPTDQRRYSST 
               
               
                   
                 PVRNKRGVFVLGFLGFLATAGSAMGARSLTLSAQSR 
               
               
                   
                 TLLAGIVQQQQQLLDVVKRQQEMLRLTVWGTKNLQA 
               
               
                   
                 RVT AIEKYRKHQ AQLNSWGCAFRQVCHTTVPWVNDS 
               
               
                   
                 LSPDWKNMTWQEWEKQVRYLEANISQSLEEAQIQQE 
               
               
                   
                 KNMYELQKLNSWDILGNWFDLTSWVKYIQYGVHIVV 
               
               
                   
                 GIIALRIAIYVVQLLSRFRKGYRPVFSSPPGYLQQI 
               
               
                   
                 HIHKDRGQPANEGTEEDVGGDSGYDLWPWPINYVQF 
               
               
                   
                 LIHLLTRLLIGLYNICRDLLSKNSPTRRLISQSLTA 
               
               
                   
                 IRDWLRLKAAQLQYGCEWIQEAFQAFARTTRETLAG 
               
               
                   
                 AWGWLWEAARRIGRGILAVPRRIRQGAELALL 
               
               
                   
               
             
          
         
       
     
     Advantageously: the mutated lentiviral proteins are
     1—SEQ ID NO: 284 to 294; these mutated ENV proteins having substantially no immunosuppressive properties advantageously,   2—SEQ ID NO: 284 to SEQ ID NO: 292; these mutated ENV proteins having substantially no immunosuppressive properties and being highly expressed at the plasma membrane, more advantageously,   3—SEQ ID NO: 284 to SEQ ID NO: 291; these mutated ENV proteins having substantially no immunosuppressive properties, being highly expressed at the plasma membrane and conferring to a virus expressing them a medium or high viral titer, in particular   4—Y41F (SEQ ID NO: 291), Y41L (SEQ ID NO: 289), Y41A (SEQ ID NO: 290); these mutated ENV proteins having substantially no immunosuppressive properties, being highly expressed at the plasma membrane and confers to a virus expressing them a high viral titer. As mentioned above “confering to a virus expressing them a medium or high viral titer” means that, when the sequence of the wild type ENV protein is substituted by the sequence of the mutated ENV in the lentiviral or pseudotype retrovirus, the virus thus expresses a mutated lentiviral ENV protein, along with other wild type viral proteins (GAG, PRO, POL), said mutated ENV protein conferring to the virus the ability to enter in its target cell:
       either at a level comparable or higher to the ability of the wild type virus, i.e. high ability   or at a lower level compared to the ability of the wild type virus, i.e. medium or low ability.   
       

     The ability to enter in the target cell can be measured by the viral load. Viral load is a measure of the amount of target cells that can be infected by a given amount (1 mL) of virus (see  FIG. 5  and example). 
     The invention also relates to a pharmaceutical composition comprising a nucleic acid molecule coding for a mutated lentiviral ENV protein, or variant of said protein, or fragments thereof, as defined above, in association with a pharmaceutically acceptable carrier. 
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said nucleic acid is comprised in a vector, said vector comprising means allowing the expression of said mutated lentiviral ENV protein, or variant of said protein, or fragments thereof. 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said nucleic acid is comprised in a vector, said nucleic acid being placed under the control of sequences that allow the expression of said mutated lentiviral ENV protein, or variant of said protein, or fragments thereof. 
     In another embodiment, the invention relates to a pharmaceutical composition, as defined above, in particular as a vaccine, comprising a DNA molecule coding for said mutated lentiviral ENV protein, or variant of said protein, or fragments thereof. 
     DNA vaccines expressing ENV proteins can be produced as described in Bellier et al., (DNA vaccines expressing retrovirus-like particles are efficient immunogens to induce neutralizing antibodies,  Vaccine,  27(42):5772-80, 2009). 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, said vector being chosen among an eukaryotic or prokaryotic expression vector, in particular an eukaryotic vector which is a viral vector, in particular a pox vector, such as a fowlpox, a canarypox, or a MVA (modified vaccinia virus Ankara) vector, an adenoviral vector, a lentiviral vector, a measles vector, a Sendai virus or a CMV (cytomegalovirus) vector. 
     In another advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, further comprising at least one nucleotide molecule coding for a GAG and/or a PRO and/or a POL protein and/or a mutated NEF protein substantially devoid of immunosuppressive properties, of a lentivirus, preferably a lentivirus of the same origin as the mutated lentiviral ENV protein. 
     The advantageous mutated Nef protein contains a substitution at position 93, as described in the international application WO 2006/018289 (Inventors: Renard M., Mangeney M. and Heidmann T.) and a deletion of the N-terminus of the protein involved in its myristoylation. 
     GAG expression will produce virus like particles (VLPs) which are particularly advantageous for a vaccine, in particular if the ENV protein is associated with the VLP (Guerbois et al.,  Virology,  388:191-203, 2009). 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in the same vector as the one which also contains said at least one nucleic acid molecule coding for a GAG protein and/or a PRO protein and/or a POL protein and/or a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in the same vector as the one which also contains all said at least one nucleic acid molecule coding for a GAG protein and/or a PRO protein and/or a POL protein and/or a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in a vector which is different from the at least one vector containing said at least one nucleic acid molecule coding for a GAG protein and/or a PRO protein and/or a POL protein and/or a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, said nucleic acid molecule coding for a GAG protein, said nucleic acid molecule coding for a PRO protein, said nucleic acid molecule coding for a POL protein and said nucleic acid molecule coding for a mutated NEF protein substantially devoid of immunosuppressive properties, are all contained in vectors which are different from each other. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, comprising at least one nucleic acid molecule coding for a GAG protein and/or a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties,
         of a human or simian lentivirus, said lentivirus being preferably of the same origin as the mutated lentiviral ENV protein.       

     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in the same vector as the one which also contains said at least one nucleic acid molecule coding for a GAG protein and/or a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in the same vector as the one which also contains a nucleic acid molecule coding for a GAG protein and for a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in the same vector as the one which also contains a nucleic acid molecule coding for a GAG protein and for a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties, said vector being preferably a measles vector (Guerbois et al.,  Virology,  388:191-203, 2009) or a canary pox vector (Poulet et al.,  Veterinary Record,  153(5):141-145, 2003; Vaccari et al.,  Expert Review of Vaccines, Vol.  9 , No  9 , pages  997-1005, 2010). 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, is contained in a vector which is different from the at least one vector containing said at least one nucleic acid molecule coding for a GAG protein and/or a mutated NEF protein, wherein said mutated NEF protein is substantially devoid of immunosuppressive properties. 
     In another particular embodiment, the invention relates to a pharmaceutical composition, as defined above, wherein said nucleic acid molecule coding for a mutated human or simian lentiviral ENV protein, or a fragment of said mutated human or simian lentiviral ENV protein, said nucleic acid molecule coding for a GAG protein and said nucleic acid molecule coding for a mutated NEF protein substantially devoid of immunosuppressive properties, are all contained in vectors which are different from each other. 
     The invention also relates to a pharmaceutical composition according the above definition, for its use as vaccine, for the treatment or the prevention of lentiviral infection, in particular HIV-1 infection, HIV-2 infection and SIV infection. 
     As mentioned above the pharmaceutical composition according to the invention encompasses a vaccine, comprising as active substance, a protein as defined above, or a nucleic acid as defined above, or a vector as defined above, or a combination thereof. 
     In a particular embodiment, the pharmaceutical composition according to the invention encompasses a vaccine, comprising a nucleic acid coding for a GAG protein as defined above, a nucleic acid coding for a mutated ENV protein as defined above and a nucleic acid coding for a mutated NEF protein as defined above. 
     In a particular embodiment, the pharmaceutical composition according to the invention encompasses a vaccine as defined above, comprising a nucleic acid coding for a GAG protein as defined above, a nucleic acid coding for a mutated ENV protein as defined above and a nucleic acid coding for a mutated NEF protein as defined above, which are contained in a same vector, said same vector being preferably a canary pox vector or a measles vector, more preferably a measles vector. 
     In a particular embodiment, the pharmaceutical composition according to the invention encompasses a vaccine, comprising a GAG protein as defined above, a mutated ENV protein as defined above and a mutated NEF protein as defined above. 
     In a particular embodiment, the pharmaceutical composition according to the invention encompasses a vaccine, comprising a GAG protein as defined above, a mutated ENV protein as defined above and a mutated NEF protein as defined above which are associated to at least one adjuvant. 
     A comprehensive list of adjuvants that can be used in HIV vaccines is indicated in the FRANKLIN PIERCE LAW CENTER EDUCATIONAL REPORT: PATENT LANDSCAPE OF ADJUVANT FOR HIV VACCINES which is incorporated herein by reference. This list includes:
         Aluminum-based compounds such as aluminum phosphate and aluminum hydroxide.   Immunostimulatory adjuvants like CpG, MPL and QS21 or MF59 which is a squalene oil-in water emulsions.   Freunds incomplete adjuvant (FIA) or Freund&#39;s complete adjuvant (FCA), can also be used.   Calcium phosphate in particular orthophosphates, metaphosphates or pyrophosphates and occasionally hydrogen or hydroxide ions.   Muramyl dipeptide (N-Acetyl muramyl-L-alanine-D-isoglutamine, MDP) and its synthetic analogs such as muramyl tripeptide phosphatidylethanolamine MTPPTdEtn),   Trehalose-6,6′-dimycolate,   Saponins (Triterpenoid glycosides) like QS-21   Stearyl Tyrosine (octadecyl ester hydrochloride salt of tyrosine) 0.107       

     Immunostimulatory adjuvants can include the following classes of compounds:
         Polysaccharides like:
           Chitosan:   Inulin:   Beta-Glucans   Lipo-Polysaccharides or endotoxin   MGN-3 Actinidia eriantha  (AEPS):   Eldexomer:   CpG ODN   
           Liposomes like
           Dehydration-rehydration liposome vesicles (DRVs)   Cytotoxic T lymphocyte (CTL)   CAF01   Liposomes containing lipid A (LA)   
           Lipid Polysine Core Peptides (LCP)   Cytokine like GM-CSF, IL-2, IL-12 or IL-15   Lipid A and Monophosphoryl Lipid A (MPL)   Lipopeptide which are molecules consisting of lipid connected to a peptide. They are derived from the lipoprotein of bacterial cell wall.   Exogenous Immunostimulatory Adjuvants which are compounds, or proteins that are not found in the human body like:
           Proteosomes in particular Multiple Antigenic Peptides (MAP) or Exogenous Toxins   
               

     Suitably, the total amount mutated lentiviral ENV protein in a single dose of the immunogenic composition is 10 g and/or the total amount of unfused polypeptide in a single dose of the immunogenic composition is 20 g. In one embodiment, the total amount of all antigens in a single dose of the immunogenic composition is 0.5-50 μg, 2-40 μg, 5-30 μg, 10μ-20 μg or around 30 μg, around 20 μg or around 10 μg. 
     The amount of mutated lentiviral ENV protein in a dose of the immunogenic composition is selected as an amount which induces an immune response without significant, adverse side effects in typical recipients. Such amount will vary depending upon which specific immunogen is employed and the dosing or vaccination regimen that is selected. An optimal amount for a particular immunogenic composition can be ascertained by standard studies involving observation of relevant immune responses in subjects. 
     Administration of the pharmaceutical composition can take the form of one or of more than one individual dose, for example as repeat doses of the same polypeptide containing composition, or in a heterologous “prime-boost” vaccination regime, including proteins and vectors. In one embodiment, the immunogenic composition of the invention is initially administered to a subject as two or three doses, wherein the doses are separated by a period of two weeks to three months, preferably one month. 
     Conveniently, the composition is administered to a subject (for instance as a booster) every 6-24, or 9-18 months, for instance annually. For instance, the composition is administered to a subject (for instance as a booster) at six month or 1 year intervals. Suitably in this respect, subsequent administrations of the composition to the subject boost the immune response of earlier administrations of the composition to the same subject. 
     In an embodiment, the immunogenic composition of the invention is used as part of a prime-boost regimen for use in the treatment or prevention of disease or infection by HIV-1 strains from one or more clades different from the one or more HIV-1 clades in the immunogenic composition. Conveniently, the composition is the priming dose. Alternatively, the composition is the boosting dose. 
     Suitably, two or more priming and/or boosting doses are administered. A heterologous prime-boost regime uses administration of different forms of immunogenic composition or vaccine in the prime and the boost, each of which can itself include two or more administrations. The priming composition and the boosting composition will have at least one antigen in common, although it is not necessarily an identical form of the antigen, it can be a different form of the same antigen. 
     Prime boost immunisations according to the invention can be homologous prime-boost regimes or heterologous prime-boost regimes. Homologous prime-boost regimes utilize the same composition for prime and boost, for instance the immunogenic composition of the invention. Heterologous prime-boost regimes can be performed with a combination of protein and DNA-based formulations. Such a strategy is considered to be effective in inducing broad immune responses. Adjuvanted protein vaccines induce mainly antibodies and CD4+ T cell immune responses, while delivery of DNA as a plasmid or a recombinant vector induces strong CD8+ T cell responses. Thus, the combination of protein and DNA vaccination can provide for a wide variety of immune responses. This is particularly relevant in the context of HIV, since neutralizing antibodies, CD4+ T cells and CD8+ T cells are thought to be important for the immune defense against HIV-1. 
     The invention also relates to a pharmaceutical composition according the above definition, for its use for the treatment of lentiviral infection. 
     The invention also relates to a method for treating patient afflicted by pathologies related to lentiviral infection, comprising the administration to a patient in a need thereof of a pharmaceutically efficient amount of the pharmaceutical composition as defined above. 
     The invention also relates to a method for inducing an immune response against a lentivirus that has infected an individual, said method comprising the administration to a patient in a need thereof of a pharmaceutically efficient amount of the pharmaceutical composition as defined above. 
     The invention also relates to a pharmaceutical composition as defined above, further comprising an antiviral agent. 
     The composition according to the invention can also be used in combination with the antiviral compositions listed in Table 1 below: 
     
       
         
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Trade names of the different antivirals used for HIV treatment, as well as their specificity of action. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Intelence ® (TMC 125/etravirine) Tibotec - 
                 Non-nucleoside reverse transcriptase inhibitor 
               
               
                 Agenerase ® (APV/amprenavir) GSK - 
                 Protease inhibitor 
               
               
                 Aptivus ® (TPV/tipranavir) Boehringer - 
                 Protease inhibitor 
               
               
                 Crixivan ® (IDV/indinavir) MSD - 
                 Protease inhibitor 
               
               
                 Invirase ® (SQV/saquinavir) Roche - 
                 Protease inhibitor 
               
               
                 Kaletra ® (LPV.r/lopinavir + ritonavir) Abbott 
                 Protease inhibitor 
               
               
                 Norvir ® (ritonavir) Abbott - 
                 Protease inhibitor 
               
               
                 Prezista ® (TMC 114/darunavir) Tibotec/Janssen-Cilag - 
                 Protease inhibitor 
               
               
                 Reyataz ® (ATZ/atazanavir) BMS - 
                 Protease inhibitor 
               
               
                 Telzir ® (APV/fosamprenavir) GSK - 
                 Protease inhibitor 
               
               
                 Viracept ® (nelfinavir) Roche - 
                 Protease inhibitor 
               
               
                 Fuzeon ® (T20/enfuvirtide) Roche - 
                 Fusion inhibitor 
               
               
                 Celsentri ® (maraviroc) Pfizer - 
                 Entry inhibitor 
               
               
                 Isentress ® (MK 0518/raltegravir) Merck - 
                 Integrase inhibitor 
               
               
                 Rescriptor ® (delavirdine) Agouron - 
                 Non-nucleoside reverse transcriptase inhibitor 
               
               
                 Sustiva ® (EFV/efavirenz) BMS - 
                 Non-nucleoside reverse transcriptase inhibitor 
               
               
                 Viramune ® (nevirapine) Boehringer - 
                 Non-nucleoside reverse transcriptase inhibitor 
               
               
                 Combivir ® (Retrovir ® + Epivir ®) GSK - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Emtriva ® (FTC, emtricitabine) Gilead - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Epivir ® (3TC, lamivudine) GSK - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Kivexa ® (Ziagen ® + Epivir ®) GSK - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Retrovir ® (AZT/zidovudine) QSK - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Trizivir ® (Retrovir ® + Epivir ® + Ziagen ®) GSK - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Videx ® (ddI/didanosine) BMS - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Viread ® (TDF/tenofovir) Gilead - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Zerit ® (d4T/stavudine) BMS - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Ziagen ® (ABC/abacavir) GSK - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Truvada ® (Emtriva ® + Viread ®) Gilead - 
                 Nucleoside reverse transcriptase inhibitor 
               
               
                 Atripla ® (Sustiva ® + Emtriva ® + Viread ®) BMS/GILEAD 
                 Nucleoside and non-nucleoside reverse transcriptase inhibitor 
               
               
                   
               
             
          
         
       
     
     The invention also relates to a pharmaceutical composition as defined above, for simultaneous, separate or sequential use. 
     The invention relates to a pharmaceutical composition as defined above for its use for stimulating an immune response in a host organism. 
     The invention relates to a pharmaceutical composition as defined above for its use for inducing a specific immune response against the HIV ENV protein. 
     The invention relates to a pharmaceutical composition as defined above for its use for the prevention or the treatment of HIV infection, or pathologies related to AIDS. 
     The invention relates to a pharmaceutical composition as defined above, as a vaccine, for its use for inducing a specific immune response against the HIV ENV protein. 
     The invention relates to a pharmaceutical composition as defined above, as a vaccine, for its use for the prevention or the treatment of HIV infection, or pathologies related to AIDS. 
     In another aspect, the invention also relates to a method to obtain the active substance of a pharmaceutical composition, as defined above, consisting of modifying the immunosuppressive property of: 
     a wild-type human or simian lentiviral ENV protein, 
     or a fragment of said wild-type human or simian lentiviral ENV protein, said fragment comprising at least 40 amino acids, 
     said ENV protein or fragment thereof presenting a transmembrane subunit (TM) comprising an immunosuppressive domain (ISU) containing the following amino acid sequence: 
                         A-[I/V]-E-[K/R]-X′ a -X′ b -X-D-Q,   (SEQ ID NO: 427)            
wherein
 
X represents any amino acid,
 
X′ a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and
 
X′ b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y,
 
said method comprising a step of introduction of at least one mutation of X′ a  and/or X′ b , to obtain:
 
an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,
 
said mutated human or simian lentiviral ENV protein having at least 70% identity, preferably at least 80% identity, to one sequence chosen from the group consisting of SEQ ID NO: 216, SEQ ID NO: 420 and SEQ ID NO: 421,
 
or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids,
 
said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence:
 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein
 
X represents any amino acid,
 
and either
 
X a  is A, F, G, L, R or deleted, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or
 
X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G, R or deleted, or
 
X a  is A, F, G, L, R or deleted, and X b  is A, F, G, R or deleted,
 
said substantial absence of immunosuppressive activity of the above mentioned mutated human or simian lentiviral ENV protein or of the above defined fragment being liable to be assessed by the fact that in an in vivo assay involving engrafted tumor cells rejection, said tumor cells being transduced either so as to express said mutated ENV protein or said fragment (mutated ENV tumor cells),
 
or said tumor cells being transduced so as to express said wild type ENV protein or a fragment thereof (wild type ENV tumor cells),
 
or said tumor cells being not transduced (normal tumor cells), the following ratio:
 
immunosuppression index of said mutated ENV protein or of said fragment (i mutated env )/immunosuppression index of wild type ENV protein (i wild type env ) is less than 0.5,
 
i mutated env  being defined by: (maximum area reached by mutated ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells), and
 
i wild type env  being defined by: (maximum area reached by wild type ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells).
 
     The invention also relates to a method to obtain a pharmaceutical composition wherein the active substance is an isolated non naturally occurring mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, as above defined, or fragments thereof. 
     The invention also relates to a method to obtain the active substance of a pharmaceutical composition, according to the above defined method, consisting of modifying the immunosuppressive property of: 
     a wild-type human or simian lentiviral ENV protein, 
     or a fragment of said wild-type human or simian lentiviral ENV protein, said fragment comprising at least 40 amino acids, 
     said ENV protein or fragment thereof presenting a transmembrane subunit (TM) comprising an immunosuppressive domain (ISU) containing the following amino acid sequence: 
                                 A-[I/V]-E-[K/R]-Y-L-X-D-Q,   (SEQ ID NO: 1)            
wherein
 
X represents any amino acid,
 
said method comprising a step of introduction of at least one mutation of Y in position 5 and/or L in position 6,
 
to obtain:
 
an isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity,
 
or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids,
 
said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence:
 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein
 
X represents any amino acid,
 
and either
 
X a  is A, F, G, L, R or deleted, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or
 
X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G, R or deleted, or
 
X a  is A, F, G, L, R or deleted, and X b  is A, F, G, R or deleted.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein
 
X represents any amino acid,
 
and either
 
X a  is A, F, G, L or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or
 
X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is A, F, G or R, or
 
X a  is A, F, G, L or R, and X b  is A, F, G or R.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein
 
X represents any amino acid,
 
and either
 
X a  is A, F, G, L or R, and X b  is L, I, V, M or P, or
 
X a  is Y, I, H, C or T, and X b  is A, F, G or R, or
 
X a  is A, F, G, L or R, and X b  is A, F, G or R.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein
 
X represents any amino acid,
 
and either
 
X a  is A, G, or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or
 
X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is F, G or R, or
 
X a  is F or L, and X b  is F, G or R, or
 
X a  is A, G or R, and X b  is A.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein
 
X represents any amino acid,
 
and either
 
X a  is A, G, or R, and X b  is L, I, V, M or P, or
 
X a  is Y, I, H, C or T, and X b  is F, G or R, or
 
X a  is F or L, and X b  is F, G or R, or
 
X a  is A, G or R, and X b  is A, or
 
X a  is A, G or R, and X b  is F, G or R.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein,
 
X represents any amino acid,
 
and either
 
X a  is A, G, or R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or
 
X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is F, G or R.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein,
 
X represents any amino acid,
 
and either
 
X a  is A, G, or R, and X b  is L, I, V, M or P, or
 
X a  is Y, I, H, C or T, and X b  is F, G or R.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutated immunosuppressive domain (ISU) containing the following amino sequence: 
                         A-[I/V]-E-[K/R]-X a -X b -X-D-Q,   (SEQ ID NO: 416)            
wherein,
 
X represents any amino acid,
 
and either
 
X a  is R, and X b  is C, D, E, H, I, K, L, M, N, P, Q, S, T, V, W or Y, or
 
X a  is C, D, E, H, I, K, M, N, P, Q, S, T, V, W or Y, and X b  is R, or
 
X a  is R, and X b  is R.
 
     The invention also relates to a method as defined above to obtain the active substance of a pharmaceutical composition, 
     wherein said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, 
     or a fragment of said isolated mutated human or simian lentiviral ENV protein having substantially no immunosuppressive activity, said fragment comprising at least 40 amino acids, 
     said mutated ENV protein and fragment thereof comprising a mutation in one at least of the amino acids at positions, 29, 36 and 37 of SEQ ID NO: 426: 
                               (SEQ ID NO: 426)                A[I/V]E[K/R]X a X b X 1 DQX 2 X 3 LX 4 X 5 WGC[A/S]           [F/G]X 6 X 7 CVX 8 TX 9 VPX c X 10 Z 1 Z 2 Z 3 Z 4 Z 5 X d X e [S/T]            
wherein
 
X a  and X b  are as defined in anyone of claims  1  to  15 ,
 
X 1  to X 10  represent any amino acid,
 
Z 1  to Z 5  represent no amino acid or any amino acid, independently from each other such that
         X c  is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, Y, or deleted, preferably A, D, or N,   X d  is A, C, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, Y, W, or deleted, preferably A, G, S or Y,   X e  is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, Y, W, or deleted, preferably A, D or N.       

     The present invention relates to a pharmaceutical composition comprising as active substance: 
     a) an isolated non naturally occurring mutated human or simian lentiviral ENV having substantially no immunosuppressive activity, said mutated human or simian lentiviral ENV resulting from mutation of the transmembrane subunit (TM) of a wild type human or simian lentiviral ENV protein, the transmembrane subunit comprising an immunosuppressive domain (ISU) comprising the following amino acid sequence: 
                                 A-[I/V]-E-[K/R]-Y-L-X-D-Q,   (SEQ ID NO: 1)            
said sequence encompassing
 
     AIEKYLXDQ (SEQ ID NO: 2), AIERYLXDQ (SEQ ID NO: 3), AVEKYLXDQ (SEQ ID NO: 4) and AVERYLXDQ (SEQ ID NO: 5), wherein X represents any natural amino acid, 
     wherein the amino acids at the positions chosen among 
     
         
         
           
             the position 4 of SEQ ID NO: 1, 
             the position 5 of SEQ ID NO: 1, 
             the position 6 of SEQ ID NO: 1, 
             the positions 4 and 5 of SEQ ID NO: 1, 
             the position 4 and 6 of SEQ ID NO: 1, 
             the position 5 and 6 of SEQ ID NO: 1, and 
             the position 4, 5 and 6 of SEQ ID NO: 1,
 
are:
 
             either deleted, 
             or substituted by another amino acid such that
           when the immunosuppressive domain comprises SEQ ID NO: 2 or 4
               the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y,   
               when the immunosuppressive domain comprises SEQ ID NO: 3 or 5,
               the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, V, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y, or   
               
         
             b) a fragment of said mutated human or simian lentiviral ENV, said fragment comprising at least the immunosuppressive domain (ISU) of said wild type human or simian lentiviral ENV comprising the following amino acid sequence: 
           
         
       
    
                                 A-[I/V]-E-[K/R]-Y-L-X-D-Q,   (SEQ ID NO: 1)            
wherein the amino acids at the positions chosen among
         the position 4 of SEQ ID NO: 1,   the position 5 of SEQ ID NO: 1,   the position 6 of SEQ ID NO: 1,   the positions 4 and 5 of SEQ ID NO: 1,   the position 4 and 6 of SEQ ID NO: 1,   the position 5 and 6 of SEQ ID NO: 1, and   the position 4, 5 and 6 of SEQ ID NO: 1,
 
are:
   either deleted,   or substituted by another amino acid such that
           when the immunosuppressive domain comprises SEQ ID NO: 2 or 4
               the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M N, P, Q, R, S, T, V, W or Y,   
               when the immunosuppressive domain comprises SEQ ID NO: 3 or 5,
               the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M N, P, Q, R, S, T, V, W or Y,
 
said fragment having substantially no immunosuppressive properties, in association of a pharmaceutically acceptable carrier.
   
               
               

     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein the amino acids at the positions of the group consisting of
         the position 4 of SEQ ID NO: 1,   the position 5 of SEQ ID NO: 1,   the position 6 of SEQ ID NO: 1,   the positions 4 and 5 of SEQ ID NO: 1,   the position 4 and 6 of SEQ ID NO: 1,   the position 5 and 6 of SEQ ID NO: 1, and   the position 4, 5 and 6 of SEQ ID NO: 1,
           are substituted by another amino acid such that
               when the immunosuppressive domain comprises SEQ ID NO: 2 or 4
                   the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, L, M N, P, Q, R, S, T, V, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, N, P, Q, R, S, T, V, W or Y,   
                   when the immunosuppressive domain comprises SEQ ID NO: 3 or 5,
                   the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y.   
                   
               
               

     Advantageously, the mutated lentiviral protein according to the invention, comprised in the above defined composition, comprises the amino acid sequence of the list consisting of SEQ ID NO: 407 to SEQ ID NO: 414. 
     The correspondence is the following one: 
     
       
         
               
               
               
             
           
               
                   
                 AVEAALKD 
                 SEQ ID NO: 407 
               
               
                   
                   
               
               
                   
                 AVEEALKD 
                 SEQ ID NO: 408 
               
               
                   
                   
               
               
                   
                 AVESALKD 
                 SEQ ID NO: 409 
               
               
                   
                   
               
               
                   
                 AVETALKD 
                 SEQ ID NO: 410 
               
               
                   
                   
               
               
                   
                 AIEAALKD 
                 SEQ ID NO: 411 
               
               
                   
                   
               
               
                   
                 AIEEALKD 
                 SEQ ID NO: 412 
               
               
                   
                   
               
               
                   
                 AIESALKD 
                 SEQ ID NO: 413 
               
               
                   
                   
               
               
                   
                 AIETALKD 
                 SEQ ID NO: 414 
               
             
          
         
       
     
     These proteins have been mutated at position 4 of SEQ ID NO: 1, by substitution, and the amino acid at position 5 has been substituted by A. 
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein the amino acids at the positions of the group consisting of
         the position 5 of SEQ ID NO: 1,   the position 6 of SEQ ID NO: 1, and   the position 5 and 6 of SEQ ID NO: 1,
           are substituted by another amino acid such that
               the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y.   
               
               

     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said immunosuppressive domain (ISU) comprises the amino acid sequence of the group consisting of: SEQ ID NO: 4 or 5. 
     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said immunosuppressive domain (ISU) comprises the amino acid sequence SEQ ID NO: 5, and wherein
         the amino acid residue at position 5 of SEQ ID NO: 5 is substituted by A, F, G, L or R, or   the amino acid residue at position 6 of SEQ ID NO: 5 is substituted by A, F, G or R, or   the amino acid residues at position 5 and 6 of SEQ ID NO: 5 are substituted by A, F, G, or R.       

     This is the case when said ENV protein is the ENV protein of HIV 1 virus. 
     The invention also relates to a pharmaceutical composition as defined above, wherein said immunosuppressive domain (ISU) comprises the amino acid sequence SEQ ID NO: 2, and wherein
         the amino acid residue at position 5 of SEQ ID NO: 2 is substituted by A, F, G, L or R, or   the amino acid residue at position 6 of SEQ ID NO: 2 is substituted by A, F, G or R, or   the amino acid residues at position 5 and 6 of SEQ ID NO: 2 are substituted by A, F, G, or R.       

     The invention also relates to a pharmaceutical composition as defined above, wherein said immunosuppressive domain (ISU) comprises the amino acid sequence SEQ ID NO: 3, and wherein
         the amino acid residue at position 5 of SEQ ID NO: 3 is substituted by A, F, G, L or R, or   the amino acid residue at position 6 of SEQ ID NO: 3 is substituted by A, F, G or R, or   the amino acid residues at position 5 and 6 of SEQ ID NO: 3 are substituted by A, F, G, or R.       

     In one advantageous embodiment, the invention relates to a pharmaceutical composition as defined above, wherein said mutated protein further comprises the wild type amino acid sequence SEQ ID NO: 270, 
                           (SEQ ID NO: 270)            X 1 DQX 2 X 3 LX 4 X 5 WGC[A/S][F/G]X 6 X 7 CVX 8 TX 9 VPWX 10 Z 1 Z 2         Z 3 Z 4 Z 5 [N/S][E/D/N/A][S/T]            
wherein X 1 -X 10  represents any amino acid,
 
wherein Z 1  to Z 5  represent no amino acid or any natural amino acid, independently from each other,
 
said mutated lentiviral protein further comprising a mutation in one at least of the amino acids at positions 23, 30 and 31 of SEQ ID NO: 270
         said mutation being:
           either a deletion,   or a substitution such that
               the amino acid at position 25 of SEQ ID NO: 270 is substituted by A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, Y,   the amino acid at position 32 of SEQ ID NO: 270 is substituted by A, C, D, E, F, G, H, I, K, L, M, P, Q, R, T, V Y, W,   the amino acid at position 33 of SEQ ID NO: 270 is substituted by C, F, G, H, I, K, L, M, P, Q, R, S, T, V Y, W.   
               
               

     In one advantageous embodiment, the invention relates to a pharmaceutical composition comprising as active substance: 
     an isolated non naturally occurring mutated human or simian lentiviral ENV having substantially no immunosuppressive activity, said mutated human or simian lentiviral ENV resulting from mutation of a wild type human or simian lentiviral ENV protein, said wild type human or simian lentiviral ENV protein comprising the following amino acid sequence: 
                           (SEQ ID NO: 415)            A[I/V]E[K/R]YLX 1 DQX 2 X 3 LX 4 X 5 WGC[A/S][F/G]X 6 X 7 CVX 8         TX 9 VPWX 10 Z 1 Z 2 Z 3 Z 4 Z 5 [N/S][E/D/N/A][S/T],            
wherein X 1 -X 10  represents any amino acid,
 
wherein Z 1  to Z 5  represent no amino acid or any natural amino acid, independently from each other,
 
wherein the amino acids at the positions chosen among
         the position 4 of SEQ ID NO: 1,   the position 5 of SEQ ID NO: 1,   the position 6 of SEQ ID NO: 1,   the positions 4 and 5 of SEQ ID NO: 1,   the position 4 and 6 of SEQ ID NO: 1,   the position 5 and 6 of SEQ ID NO: 1, and   the position 4, 5 and 6 of SEQ ID NO: 1,
 
are:
   either deleted,   or substituted by another amino acid such that
           the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, L, M N, P, Q, S, T, V, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, N, P, Q, R, S, T, V, W or Y,
 
and further wherein
 
one at least of the amino acids at positions 29, 36 and 37 of the amino acid sequence SEQ ID NO: 415 are mutated, by
   
           either a deletion,   or a substitution such that
           the amino acid at position 29 of SEQ ID NO: 415 is substituted by A, C, D, E, F, G, H I, K, L, M, N, P, Q, R, S, T, V Y,   the amino acid at position 36 of SEQ ID NO: 415 is substituted by A, C, D, E, F, G, H, I, K, L, M, P, Q, R, T, V Y, W,   the amino acid at position 37 of SEQ ID NO: 415 is substituted by C, F, G, H, I, K, L, M, P, Q, R, S, T, V Y, W   
               

     In another aspect, the invention relates to a pharmaceutical composition as defined above, further comprising a mutation at the position X 4   
                           (SEQ ID NO: 270)            X 1 DQX 2 X 3 LX 4 X 5 WGC[A/S][F/G]X 6 X 7 CVX 8 TX 9 VPWX 10 Z 1 Z 2 Z 3         Z 4 Z 5 [N/S][E/D/N/A][S/T]            
wherein X—X 3  and X 5 -X 10  represents any amino acid,
 
Z 1  to Z 5  represent no amino acid or any amino acid, independently from each other
         said mutation being:
           either a deletion,   or a substitution by A, C, D, E, F, H, I, K, L, M, P, Q, R, S, T, V, Y or W   
               

     In one advantageous embodiment, the invention relates to a pharmaceutical composition comprising as active substance: 
     an isolated non naturally occurring mutated human or simian lentiviral ENV having substantially no immunosuppressive activity, said mutated human or simian lentiviral ENV resulting from mutation of a wild type human or simian lentiviral ENV protein, said wild type human or simian lentiviral ENV protein comprising the following amino acid sequence: 
                           (SEQ ID NO: 415)            A[I/V]E[K/R]YLX 1 DQX 2 X 3 LX 4 X 5 WGC[A/S][F/G]X 6 X 7 CVX 8         TX 9 VPWX 10 Z 1 Z 2 Z 3 Z 4 Z 5 [N/S][E/D/N/A][S/T],            
wherein X 1 -X 10  represents any amino acid,
 
wherein Z 1  to Z 5  represent no amino acid or any natural amino acid, independently from each other,
 
wherein the amino acids at the positions chosen among
         the position 4 of SEQ ID NO: 1,   the position 5 of SEQ ID NO: 1,   the position 6 of SEQ ID NO: 1,   the positions 4 and 5 of SEQ ID NO: 1,   the position 4 and 6 of SEQ ID NO: 1,   the position 5 and 6 of SEQ ID NO: 1, and   the position 4, 5 and 6 of SEQ ID NO: 1,
 
are:
   either deleted,   or substituted by another amino acid such that
           the amino acid residue at position 4 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, L, M N, P, Q, S, T, V, W or Y, and/or   the amino acid residue at position 5 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, I, L, M, N, P, Q, R, S, T, V or W, and/or   the amino acid residue at position 6 of SEQ ID NO: 1 is substituted by A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y,
 
and possibly, further wherein
 
one at least of the amino acids at positions 29, 36 and 37 of the amino acid sequence SEQ ID NO: 415 are mutated, by
   
           either a deletion,   or a substitution such that
           the amino acid at position 29 of SEQ ID NO: 415 is substituted by A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V Y,   the amino acid at position 36 of SEQ ID NO: 415 is substituted by A, C, D, E, F, G, H, I, K, L, M, P, Q, R, T, V, Y, W,   the amino acid at position 37 of SEQ ID NO: 415 is substituted by C, F, G, H, I, K, L, M, P, Q, R, S, T, V, Y, W,
 
and/or possibly further wherein the amino acid at position X 4  is either deleted or substituted by A, C, D, E, F, H, I, K, L, M P, Q, R, S, T, V, Y or W, preferably by R or H.
   
               

    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1 : 
       Amino acid sequences of the HIV ectodomain deletants, with the indicated length, and of single mutant (substitution are underlined) ectodomains. 
         FIG. 2 : 
       Functional delineation of the immunosuppressive domain of the HIV envelope. The immunosuppressive activity of 115 aa-long and truncated HIV envelope ectodomains (see structures on the left) was tested using the MCA205 tumor rejection in vivo assay. Immunosuppression indexes are given as histograms on the right (mean values+/−SD). 
         FIG. 3 : 
       Functional identification of the aminoacid in the HIV envelope ectodomain directly involved in immunosuppressive activity, and search for aminoacid substitutions inhibiting this activity. Immunosuppresive activity was tested in vivo as in  FIG. 2 . 
         FIG. 4 : 
       Expression profile of mutated HIV envelopes using full-length HIV env-expressing vectors and an anti-SU HIV env(110H) monoclonal antibody (FACS). The data are expressed as percentages of the control HIV env WT. 
         FIG. 5 : 
       Infectivity of HIV env-pseudotyped viral particles showing functionality of the full-length WT and of specifically mutated HIV envelopes. The results are expressed as viral titers (number of infected target cells/mL of virus supematant). 
         FIG. 6 : 
       Functional identification of the amino acid in the SIV envelope ectodomain directly involved in immunosuppressive activity, and search for aminoacid substitutions inhibiting this activity. Immunosuppressive activity was tested using the in vivo MCA205 tumor rejection assay. Immunosuppression indexes are represented as histograms (mean values+/−SD). 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Example 
     Immunosuppressive domains have been identified on the envelope proteins of oncoretroviruses, of either the gamma-(murine MLV) or the delta (e.g. human HTLV) type, as well as of some endogenous retroviruses (e.g. HERV-FRD). These domains have a highly conserved crystallographic structure, although their primary sequences are quite diverse, and an amino-acid (either Q, E, or K) at a definite position has previously been demonstrated to be essential for the immunosuppresive activity of the corresponding envelope protein. Mutation of this amino acid to an Arginine (R) was further demonstrated to result in inhibition of the immunosuppressive activity of the mutated envelope protein, with in some cases complete conservation of the other functional properties of the envelope protein, including its ability to be normally expressed at the cell membrane, to be captured by a nascent retroviral particle, and finally to confer infectivity of the mutant virus in vitro. Such mutants allowed an unambiguous demonstration of the essential role of the immunosuppressive activity for viremia in vivo, with the mutant IS-virus being unable to escape the host immune system and propagate in an immunocompetent animal [Schlecht-Louf et al.,  Proc Natl Acad Sci USA.  2010; 107(8): 3782-7]. 
     On the basis of the identification of an IS domain and on the ability of the IS function to be inhibited by specific mutations within the IS domain that do not disrupt the antigenic structure of the corresponding viral protein, vaccinal approaches are being developed with vaccines containing mutated            optimized           IS-negative viral antigens, which demonstrate an increased immunognicity as compared to those using the native viral antigens. Search for similar IS domains and appropriate mutations in the case of non-oncogenic—but still pathogenic-retroviruses such as HIV is therefore of interest to tentatively develop improved vaccines.
     Actually, in the case of the other major class of retroviruses, namely the lentiviruses (among which the human HIV1 and HIV2, and the SIV simian homologues), the crystallographic structure of the envelope protein discloses some similarities but also very important differences, especially in the domain corresponding to the IS domain of oncoretroviruses, with evidence in HIV and SIV for a severely extended helix-loop-helix domain, and no evidence for sequence similarities with the IS domain of oncoretroviruses. 
     Furthermore, an IS domain with strong amino-acid similarities with the IS domain of oncoretroviruses was identified within an accessory protein of HIV and SIV, namely within the Nef protein. This protein is specifically produced by these complex retroviruses and is not encoded by oncoretroviruses. The Nef protein is essential for viremia in vivo, and it possesses several domains responsible for immune escape, among which the identified IS domain, thus strongly suggesting that lentiviruses had transferred the immunosuppressive activity found in oncoretroviruses within their envelope protein, to the accessory Nef protein. In agreement with this hypothesis, Nef-deleted or Nef-mutated retroviruses have a severely attenuated pathogenicity in in vivo macaque animal models. 
     Here, the Inventors report on the identification of an IS activity carried by the HIV and SIV envelope proteins, and on specific mutations that inhibit this activity without major disrupt ion of the overall structure of the corresponding envelope proteins. 
     Results 
     Delination of the Immunosuppressive Domain of the HIV Envelope 
     Delineation of the immunosuppressive domain of the HIV envelope was achieved using an in vivo tumor rejection assay, that the Inventors had previously used to demonstrate the immunosuppressive activity of the Env protein of oncoretroviruses (murine MoMLV and simian MPMV). The rationale of the assay can be summarized as follows: while injection of MCA205 tumor cells (H-2 b ) into allogeneic Balb/c mice (H-2 d ) leads to the formation of no tumor or transient tumors that are rapidly rejected, injection of the same cells, but stably expressing an immunosuppressive retroviral Env protein, leads to the growth of larger tumors that persist for a longer time—in spite of the expression of the new exogenous antigen. This difference is not associated with a difference in intrinsic cell growth rate since it is not observed in syngeneic C57BL/6 mice, and is immune system-dependent. The extent of “immunosuppression” can be quantified by an index based on tumor size: (A env -A none )/A none , where A env  and A none  are the mean areas at the peak of growth of tumors from Balb/c mice injected with env-expressing or control cells, respectively. A positive index indicates that env expression facilitates tumor growth, as a consequence of its immunosuppressive activity; a null or negative index points to no effect or even an inhibitory effect, respectively. The latter may be explained by a stimulation of the immune response of the host against the new foreign antigen, represented by a non-immunosuppressive Env protein, expressed at the surface of tumor cells. 
     To first delineate a minimal immunosuppressive domain (ISD) active in vivo, the Inventors analyzed the effect of a series of truncations/deletions within the HIV env gene. Assay of the series of C-term truncations in  FIGS. 1&amp;2  identified a 49 residue-long domain with IS activity, with the 6 aa shorter HIV43 fragment and subsequent C-term truncated HIV37 and HIV30 fragments being IS-negative. HIV49 is embedded into the so-called ectodomain, which corresponds to a soluble part of the extracellular domain of the TM subunit, and consists in the a-helical domain involved in HIV TM trimerization, and the N-term part of the loop containing the 2 well-conserved, 6 aa-distant, cysteine residues found in most retroviral envelopes. Refine delineation of the amino acis responsible for IS activity was then performed by arginine-scanning between aa 36 and 51, i.e. in the domain associated with the transition from IS positive to negative Env subdomains. As illustrated in  FIG. 3 , all the X-to-Arg substitutions resulted in no significant change in the IS activity of HIV115, with one exception for Y41 and L42, which resulted in loss of IS activity of the mutant peptide. 
     Mutations at Position 41 
     The Inventors then checked that the Y41R substitution did not alter the overall capacity of the HIV envelope to be expressed by an eucaryotic cell and to be exported at the cell membrane, by introducing the Y41R substitution into an expression vector for the HIV envelope. A FACS analysis of cell transfected with both the wild-type and the Y41R mutant using an anti-SU specific monoclonal antibody actually demonstrated quantitative expression of the mutant envelope at the cell surface, thus indicating that the Y41R mutation does not significantly alter the HIV Env structure and SU-TM interaction ( FIG. 4 ). 
     A series of distinct substitutions at the Y41 position were finally performed to tentatively identify whether other amino acids could be substituted to generate IS-negative variants: the amino acid assayed included the positively charged K and H (in addition to R), the small A and G, and the hydrophobic L and F residues. Again it was checked that these substitutions did not alter the overall structure of the HIV Env with the corresponding mutations. 
     Among them, substitution of Y41 by A, G, L and F resulted in loss of IS ( FIG. 3 ), and did not alter the overall structure of the HIV Env with the corresponding mutations ( FIGS. 4 and 5 ). 
     Further Mutation Outside of the ISU Domain 
     The effects of a set of second mutations at positions that are structurally close to Y41 position within the ENV ectodomain three-dimensional structure were also tested. Two of them (Y41R-K72A and Y41R-K78G) maintain a high level expression at cell membrane and confer infectivity ( FIG. 5 ). 
     Mutations at Position 42 
     Interestingly, the adjacent position to the position Y41, position L42, also resulted in loss of IS activity of the mutant peptide when the mutation L42R is introduced. This mutation maintains a high level expression at cell membrane of the mutated HIV ENV protein ( FIG. 4 ). 
     Mutations within the SIV ENV Protein 
     Interestingly, mutation at the homologous position in SIV ENV (L42) of the position L42 in HIV-1 ENV ectodoamin also resulted in specific loss of IS activities ( FIG. 6 ). 
     Accordingly, the present investigation has clearly identified a definite location and a definite substitution(s) within the HIV env resulting in the loss of its IS activity. Being compatible with the conservation of the overall structure of the human and simian lentiviral Env proteins, these substitutions should be introduced in all pharmaceutical preparations which include the Env protein as a vaccine antigen. 
     Materials and Methods 
     Mice and cell lines: C57Bl/6 and Balb/c mice, 6-10 weeks old, were obtained from CER Janvier (Laval, France). Mice were maintained in the animal facility of the Gustave Roussy Institute in accordance with institutional regulations. 293T (ATCC CRL11268), and MCA205 cells were cultured in DMEM supplemented with 10% fetal calf serum (Invitrogen), streptomycin (100 μg/ml) and penicillin (100 units/ml). 
     Plasmid Construction: 
     The PCEL/E160 encoding the envelope protein of the BRU/LAI HIV-1 isolate is a gift from Dr Marc Sitbon. To generate the pDFG plasmids encoding the various fragments of HIV-1 envelope ectodomain, PCR fragments generated using PCEL/E160 as a template and primer pairs 1-2 (pDFG-HIV115), 1-3 (pDFG-HIV81), 1-4 (pDFG-HIV67), 1-5 (pDFG-HIV55), 1-6 (pDFG-HIV49), 1-7 (pDFG-HIV43), 1-8 (pDFG-HIV37), 1-9 (pDFG-HIV30) were digested with SfiI and MluI and inserted into pDFG-ectoSyncytin-1 (Mangeney et al, 2007) opened with the same enzymes. 
     Mutated pDFG-HIV115 were obtained by successive PCR using appropriate primers. A first series of PCR was performed with pDFG HIV115 as template using primers 1-11 and 10-2, 1-13 and 12-2, 1-15 and 14-2 or 1-17 and 16-2 to introduce the E39R, Y41R, K43R or D44R mutations respectively, and primers 1-18 and 19-2, 1-20 and 21-2, 1-22 and 23-2, 1-24 and 25-2, 1-26 and 27-2, 1-28 and 29-2, 1-30 and 31-2, 1-32 and 33-2, 1-34 and 35-2, or 1-36 and 37-2 to introduce the L36R, A37R, V38R, L42R, Q45R, Q46R, L47R, L48R, G49R, or I50R mutations respectively. The PCR products were then used as templates in subsequent PCR using primers 1-2. These PCR fragments were digested with SfiI and MluI and inserted into pDFG-ectoSyncytin-1 (Mangeney et al, 2007) opened with the same enzymes. 
     All the constructions were sequenced before use. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Primer list 
               
             
          
           
               
                 N o   
                 Name 
                 Primer sequence (5′-3′) 
                 SEQ ID 
               
               
                   
               
             
          
           
               
                 1 
                 TM HIV Sfi-Sens 
                 ACATggcccagccggccTCTGGTATAGTGCAGCAGC 
                 SEQ ID NO: 295 
               
               
                   
               
               
                 2 
                 TM HIV115 Mlu-AS 
                 GTATacgcgtTTATAATTCTTGTTCATTCTTTTC 
                 SEQ ID NO: 296 
               
               
                   
               
               
                 3 
                 TM HIV81 Mlu AS 
                 GTATacgcgtTTACATGTTATTCCAAATCTGTTCC 
                 SEQ ID NO: 297 
               
               
                   
               
               
                 4 
                 TM HIV67 Mlu AS 
                 GTATacgcgtTTAAGCATTCCAAGGCACAGC 
                 SEQ ID NO: 298 
               
               
                   
               
               
                 5 
                 TM HIV55 Mlu AS 
                 GTATacgcgtTTATCCAGAGCAACCCCAAATCC 
                 SEQ ID NO: 299 
               
               
                   
               
               
                 6 
                 TMHIV49 Mlu AS 
                 GTATacgcgtTTACCCCAGGAGCTGTTGATCC 
                 SEQ ID NO: 300 
               
               
                   
               
               
                 7 
                 TMHIV43 Mlu AS 
                 GTATacgcgtTTACTTTAGGTATCTTTCCACAGC 
                 SEQ ID NO: 301 
               
               
                   
               
               
                 8 
                 TMHIV37 Mlu AS 
                 GTATacgcgtTTAAGCCAGGATTCTTGCCTGGAG 
                 SEQ ID NO: 302 
               
               
                   
               
               
                 9 
                 TMHIV30 Mlu AS 
                 GTATacgcgtTTACTGCTTGATGCCCCAGAC 
                 SEQ ID NO: 303 
               
               
                   
               
               
                 18 
                 TMHIV115 L36R as 
                 CTTTCCACAGCCcGGATTCTTGCCTG 
                 SEQ ID NO: 304 
               
               
                   
               
               
                 19 
                 TMHIV115 L36R s 
                 CAGGCAAGAATCCgGGCTGTGGAAAG 
                 SEQ ID NO: 305 
               
               
                   
               
               
                 20 
                 TMHIV115 A37R as 
                 GTATCTTTCCACAcgCAGGATTCTTGCC 
                 SEQ ID NO: 306 
               
               
                   
               
               
                 21 
                 TMHIV115 A37R s 
                 GGCAAGAATCCTGcgTGTGGAAAGATAC 
                 SEQ ID NO: 307 
               
               
                   
               
               
                 22 
                 TMHIV115 V38R as 
                 CTTTAGGTATCTTTCCctAGCCAGGATTCTTGCC 
                 SEQ ID NO: 308 
               
               
                   
               
               
                 23 
                 TMHIV115 V38R s 
                 GGCAAGAATCCTGGCTagGGAAAGATACCTAAAG 
                 SEQ ID NO: 309 
               
               
                   
               
               
                 11 
                 TMHIV115 E39R AS 
                 CCTTTAGGTATCTTctCACAGCCAGGATTC 
                 SEQ ID NO: 310 
               
               
                   
               
               
                 10 
                 TMHIV115 E39R S 
                 GAATCCTGGCTGTGagAAGATACCTAAAGG 
                 SEQ ID NO: 311 
               
               
                   
               
               
                 13 
                 TMHIV115 Y41R AS 
                 GTTGATCCTTTAGGcgTCTTTCCACAGCCAG 
                 SEQ ID NO: 312 
               
               
                   
               
               
                 12 
                 TMHIV115 Y41R S 
                 CTGGCTGTGGAAAGAcgCCTAAAGGATCAAC 
                 SEQ ID NO: 313 
               
               
                   
               
               
                 24 
                 TMHIV115 L42R as 
                 GGAGCTGTTGATCCTTTcGGTATCTTTCCACAGCC 
                 SEQ ID NO: 314 
               
               
                   
               
               
                 25 
                 TMHIV115 L42R s 
                 GGCTGTGGAAAGATACCgAAAGGATCAACAGCTCC 
                 SEQ ID NO: 315 
               
               
                   
               
               
                 15 
                 TMHIV115 K43R AS 
                 GAGCTGTTGATCCcTTAGGTATCTTTCCAC 
                 SEQ ID NO: 316 
               
               
                   
               
               
                 14 
                 TMHIV115 K43R S 
                 GTGGAAAGATACCTAAgGGATCAACAGCTC 
                 SEQ ID NO: 317 
               
               
                   
               
               
                 17 
                 TMHIV115 D44R AS 
                 AGGAGCTGTTGAcgCTTTAGGTATCTTT 
                 SEQ ID NO: 318 
               
               
                   
               
               
                 16 
                 TMHIV115 D44R S 
                 AAAGATACCTAAAGcgTCAACAGCTCCT 
                 SEQ ID NO: 319 
               
               
                   
               
               
                 26 
                 TMHIV115 Q45R as 
                 CCCAGGAGCTGTcGATCCTTTAGGTATC 
                 SEQ ID NO: 320 
               
               
                   
               
               
                 27 
                 TMHIV115 Q45R s 
                 GATACCTAAAGGATCgACAGCTCCTGGG 
                 SEQ ID NO: 321 
               
               
                   
               
               
                 28 
                 TMHIV115 Q46R as 
                 CAAATCCCCAGGAGCcGTTGATCCTTTAG 
                 SEQ ID NO: 322 
               
               
                   
               
               
                 29 
                 TMHIV115 Q46R s 
                 CTAAAGGATCAACgGCTCCTGGGGATTTG 
                 SEQ ID NO: 323 
               
               
                   
               
               
                 30 
                 TMHIV115 L47R as 
                 CAAATCCCCAGGcGCTGTTGATCCTTTAG 
                 SEQ ID NO: 324 
               
               
                   
               
               
                 31 
                 TMHIV115 L47R s 
                 CTAAAGGATCAACAGCgCCTGGGGATTTG 
                 SEQ ID NO: 325 
               
               
                   
               
               
                 32 
                 TMHIV115 L48R as 
                 CCCAAATCCCCcGGAGCTGTTG 
                 SEQ ID NO: 326 
               
               
                   
               
               
                 33 
                 TMHIV115 L48R s 
                 CAACAGCTCCgGGGGATTTGGG 
                 SEQ ID NO: 327 
               
               
                   
               
               
                 34 
                 TMHIV115 G49R as 
                 CCCCAAATCCgCAGGAGCTGTTG 
                 SEQ ID NO: 328 
               
               
                   
               
               
                 35 
                 TMHIV115 G49R s 
                 CAACAGCTCCTGcGGATTTGGGG 
                 SEQ ID NO: 329 
               
               
                   
               
               
                 36 
                 TMHIV115 150R as 
                 GCAACCCCAtcTCCCCAGGAGCTG 
                 SEQ ID NO: 330 
               
               
                   
               
               
                 37 
                 TMHIV115 150R s 
                 CAGCTCCTGGGGAgaTGGGGTTGC 
                 SEQ ID NO: 331 
               
               
                   
               
               
                 38 
                 TMHIV115 W51R as 
                 GCAACCCCAtcTCCCCAGGAGCTG 
                 SEQ ID NO: 332 
               
               
                   
               
               
                 39 
                 TMHIV115 W51R s 
                 CAGCTCCTGGGGAgaTGGGGTTGC 
                 SEQ ID NO: 333 
               
               
                   
               
             
          
         
       
     
     HIV115 Y41 Mutant Construction: 
     To explore the amino acid sequence necessary for the loss of immunosuppression, HIV115 Y41 mutants were produced by PCR using the pDFG HIV115 WT plasmid as template and pairs of primers 1-42 and 43-2, 1-44 and 45-2, 1-46 and 47-2, 1-48 and 49-2, 1-50 and 51-2, or 1-52 and 53-2, to introduce the Y41K, Y41H, Y41A, Y41G, Y41F, or Y41L mutations respectively. The PCR products were then used as templates in subsequent PCR using primers 1-2. These PCR fragments were digested with SfiI and MluI and inserted into pDFG-ectoSyncytin-1 (Mangeney et al, 2007) opened with the same enzymes 
     All the constructions were sequenced before use. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 N o   
                 Name 
                 Primer sequence (5′-3′) 
                 SEQ ID NO 
               
               
                   
               
             
             
               
                 42 
                 TMHIV115 Y41K as 
                 GTTGATCCTTTAGtTtTCTTTCCACAGCCAG 
                 SEQ ID NO: 334 
               
               
                   
               
               
                 43 
                 TMHIV115 Y41K s 
                 CTGGCTGTGGAAAGAaAaCTAAAGGATCAAC 
                 SEQ ID NO: 335 
               
               
                   
               
               
                 44 
                 TMHIV115 Y41H as 
                 GTTGATCCTTTAGGTgTCTTTCCACAGCCAG 
                 SEQ ID NO: 336 
               
               
                   
               
               
                 45 
                 TMHIV115 Y41H s 
                 CTGGCTGTGGAAAGAcACCTAAAGGATCAAC 
                 SEQ ID NO: 337 
               
               
                   
               
               
                 46 
                 TMHIV115 Y41A as 
                 GTTGATCCTTTAGGgcTCTTTCCACAGCCAG 
                 SEQ ID NO: 338 
               
               
                   
               
               
                 47 
                 TMHIV115 Y41A s 
                 CTGGCTGTGGAAAGAgcCCTAAAGGATCAAC 
                 SEQ ID NO: 339 
               
               
                   
               
               
                 48 
                 TMHIV115 Y41G as 
                 GTTGATCCTTTAGGccTCTTTCCACAGCCAG 
                 SEQ ID NO: 340 
               
               
                   
               
               
                 49 
                 TMHIV115 Y41G s 
                 CTGGCTGTGGAAAGAggCCTAAAGGATCAAC 
                 SEQ ID NO: 341 
               
               
                   
               
               
                 50 
                 TMHIV115 Y41F as 
                 GTTGATCCTTTAGGaATCTTTCCACAGCCAG 
                 SEQ ID NO: 342 
               
               
                   
               
               
                 51 
                 TMHIV115 Y41F s 
                 CTGGCTGTGGAAAGATtCCTAAAGGATCAAC 
                 SEQ ID NO: 343 
               
               
                   
               
               
                 52 
                 TMHIV115 Y41L as 
                 GTTGATCCTTTAGGagTCTTTCCACAGCCAG 
                 SEQ ID NO: 344 
               
               
                   
               
               
                 53 
                 TMHIV115 Y41L s 
                 CTGGCTGTGGAAAGActCCTAAAGGATCAAC 
                 SEQ ID NO: 345 
               
               
                   
               
             
          
         
       
     
     HIV115 Y41 Double Mutants Construction: 
     HIV115 Y41R K72A, G or S double mutants were produced by PCR using the pDFG HIV115 Y41R plasmid as template and pairs of primers 1-94 and 93-2, 1-96 and 95-2, or 1-98 and 97-2. The PCR products were then used as templates in subsequent PCR using primers 1-2. These PCR fragments were digested with SfiI and MluI and inserted into pDFG-ectoSyncytin-1 (Mangeney et al, 2007) opened with the same enzymes. HIV115 R40X Y41R double-mutants were produced by PCR using the pDFG HIV115 Y41R as template and pairs of primers 1-54 and 55-2, 1-56 and 57-2 to introduce the R40A and R40E mutations respectively. HIV115 R40X Y41A double-mutants were produced by PCR using the pDFG HIV115 Y41A as template and pairs of primers 1-58 and 59-2, 1-60 and 61-2, 1-62 and 63-2, 1-64 and 65-2 to introduce the R40A, R40E, R40S, R40T mutations respectively. HIV115 R40X simple mutants were also generated using pDFG HIV 115 WT as template and pairs of primers 1-66 and 67-2, 1-68 and 69-2, 1-70 and 71-2, 1-72 and 73-2. 
     The PCR products were then used as templates in subsequent PCR using primers 1-2. These PCR fragments were digested with SfiI and MluI and inserted into pDFG-ectoSyncytin-1 (Mangeney et al, 2007) opened with the same enzyme. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 N o   
                 Name 
                 Primer sequence (5′-3′) 
                 SEQ ID 
               
               
                   
               
             
             
               
                 54 
                 TM HIV115 
                 CTGGCTGTGGAAgcAcgCCTAAAGGATCAAC 
                 SEQ ID NO: 378 
               
               
                   
                 R40AY41R-S 
               
               
                   
               
               
                 55 
                 TM HIV115 
                 GTTGATCCTTTAGGcgTgcTTCCACAGCCAG 
                 SEQ ID NO: 379 
               
               
                   
                 R40AY41R-AS 
               
               
                   
               
               
                 56 
                 TM HIV115 
                 CTGGCTGTGGAAgaAcgCCTAAAGGATCAAC 
                 SEQ ID NO: 380 
               
               
                   
                 R40EY41R-S 
               
               
                   
               
               
                 57 
                 TM HIV115 
                 GTTGATCCTTTAGGcgTtcTTCCACAGCCAG 
                 SEQ ID NO: 381 
               
               
                   
                 R40EY41R-AS 
               
               
                   
               
               
                 58 
                 TM HIV115 
                 CTGGCTGTGGAAgctgcCCTAAAGGATCAAC 
                 SEQ ID NO: 382 
               
               
                   
                 R40AY41A-S 
               
               
                   
               
               
                 59 
                 TM HIV115 
                 GTTGATCCTTTAGGgcagcTTCCACAGCCAG 
                 SEQ ID NO: 383 
               
               
                   
                 R40AY41A-AS 
               
               
                   
               
               
                 60 
                 TM HIV115 
                 CTGGCTGTGGAAgaagcCCTAAAGGATCAAC 
                 SEQ ID NO: 384 
               
               
                   
                 R40EY41A-S 
               
               
                   
               
               
                 61 
                 TM HIV115 
                 GTTGATCCTTTAGGgcttcTTCCACAGCCAG 
                 SEQ ID NO: 385 
               
               
                   
                 R40EY41A-AS 
               
               
                   
               
               
                 62 
                 TM HIV115 
                 CTGGCTGTGGAAagcgcCCTAAAGGATCAAC 
                 SEQ ID NO: 386 
               
               
                   
                 R40SY41A-S 
               
               
                   
               
               
                 63 
                 TM HIV115 
                 GTTGATCCTTTAGGgcgctTTCCACAGCCAG 
                 SEQ ID NO: 387 
               
               
                   
                 R40SY41A-AS 
               
               
                   
               
               
                 64 
                 TM HIV115 
                 CTGGCTGTGGAAacagcCCTAAAGGATCAAC 
                 SEQ ID NO: 388 
               
               
                   
                 R40TY41A-S 
               
               
                   
               
               
                 65 
                 TM HIV115 
                 GTTGATCCTTTAGGgctgtTTCCACAGCCAG 
                 SEQ ID NO: 389 
               
               
                   
                 R40TY41A-AS 
               
               
                   
               
               
                 66 
                 TM HIV115 R40A-S 
                 CTGGCTGTGGAAgctTACCTAAAGGATCAAC 
                 SEQ ID NO: 390 
               
               
                   
               
               
                 67 
                 TM HIV115 R40A- 
                 GTTGATCCTTTAGGTAagcTTCCACAGCCAG 
                 SEQ ID NO: 391 
               
               
                   
                 AS 
               
               
                   
               
               
                 68 
                 TM HIV115 R40E-S 
                 CTGGCTGTGGAAgaaTACCTAAAGGATCAAC 
                 SEQ ID NO: 392 
               
               
                   
               
               
                 69 
                 TM HIV115 R40E- 
                 GTTGATCCTTTAGGTAttcTTCCACAGCCAG 
                 SEQ ID NO: 393 
               
               
                   
                 AS 
               
               
                   
               
               
                 70 
                 TM HIV115 R40S-S 
                 CTGGCTGTGGAAagcTACCTAAAGGATCAAC 
                 SEQ ID NO: 394 
               
               
                   
               
               
                 71 
                 TM HIV115 R40S- 
                 GTTGATCCTTTAGGTAgctTTCCACAGCCAG 
                 SEQ ID NO: 395 
               
               
                   
                 AS 
               
               
                   
               
               
                 72 
                 TM HIV115 R40T-S 
                 CTGGCTGTGGAAacaTACCTAAAGGATCAAC 
                 SEQ ID NO: 396 
               
               
                   
               
               
                 73 
                 TM HIV115 R40T- 
                 GTTGATCCTTTAGGTAtgtTTCCACAGCCAG 
                 SEQ ID NO: 397 
               
               
                   
                 AS 
               
               
                   
               
               
                 93 
                 TMHIV115 K72A s 
                 GCTAGTTGGAGTAATgcATCTCTGGAACAGATTTGG 
                 SEQ ID NO: 398 
               
               
                   
               
               
                 94 
                 TMHIV115 K72A 
                 CCAAATCTGTTCCAGAGATgcATTACTCCAACTAGC 
                 SEQ ID NO: 399 
               
               
                   
                 as 
               
               
                   
               
               
                 95 
                 TMHIV115 K72G s 
                 GCTAGTTGGAGTAATggATCTCTGGAACAGATTTGG 
                 SEQ ID NO: 400 
               
               
                   
               
               
                 96 
                 TMHIV115 K72G 
                 CCAAATCTGTTCCAGAGATccATTACTCCAACTAGC 
                 SEQ ID NO: 401 
               
               
                   
                 as 
               
               
                   
               
               
                 97 
                 TMHIV115 K72S s 
                 GCTAGTTGGAGTAATtcATCTCTGGAACAGATTTGG 
                 SEQ ID NO: 402 
               
               
                   
               
               
                 98 
                 TMHIV115 K72S 
                 CCAAATCTGTTCCAGAGATgaATTACTCCAACTAGC 
                 SEQ ID NO: 403 
               
               
                   
                 as 
               
               
                   
               
             
          
         
       
     
     Introduction of HIV115 Mutations into an HIV Env Expression Vector: 
     To introduce these HIV envelope mutations into the HIV env pTr712 expression vector (Schnierle et al PNAS 1997), a silent mutation was first generated to create an SfiI insertion site. PCR fragments were generated using pTr712 as a template and primer pairs 38-39 and 40-41. The PCR products were then used as templates in subsequent PCR using primers 38-41. The resulting PCR fragment was then digested with BsaBI and HindIII and inserted into the pTr712 plasmid opened with the same enzymes resulting in the pTr712-Sfi plasmid. PCR fragments of each HIV115 mutation were then generated by using primers 40-41 and the pDFG HIV115 mutant plasmids as templates, digestion with SfiI and HindIII and then insertion into the pTr712-Sfi plasmid opened with the same enzymes. 
     All the constructions were sequenced before use. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 N o   
                 Name 
                 Primer sequence (5′-3′) 
                 SEQ ID NO 
               
               
                   
               
             
             
               
                 38 
                 HIV BH10 BsaBI s 
                 acaaattagatgttcatcaaatattacaggg 
                 SEQ ID NO: 346 
               
               
                   
               
               
                 39 
                 HIV BH10 SfiI mutsil as 
                 GCAACAGATGCTGTTGgGCCTCAATgGCCCTCAGCA 
                 SEQ ID NO: 347 
               
               
                   
                   
                 AATTGTTC 
               
               
                   
               
               
                 40 
                 HIV BH10 SfiI mutsil s 
                 GAACAATTTGCTGAGGGCcATTGAGGCcCAACAGCA 
                 SEQ ID NO: 348 
               
               
                   
                   
                 TCTGTTGC 
               
               
                   
               
               
                 41 
                 HIV BH10 HindIII as 
                 gtgtattaagcttgtgtaattgttaatttctc 
                 SEQ ID NO: 349 
               
               
                   
               
               
                 74 
                 EnvHIVTr712-Xho-Age-Kozak-S 
                 NNNNNCTCGAGACCGGTccaactagaaccATGAGAGTGA 
                 SEQ ID NO: 404 
               
               
                   
                   
                 AGGAGAAATATCAGC 
               
               
                   
               
               
                 75 
                 EnvHIVTr712-Mlu-AS 
                 NNNNNACGCGTTCAATATCCCTGCCTAACTC 
                 SEQ ID NO: 405 
               
               
                   
               
               
                 76 
                 EnvHIVWT-Mlu-AS 
                 NNNNNACGCGTTTATAGCAAAATCCTTTCCAAGC 
                 SEQ ID NO: 406 
               
               
                   
               
             
          
         
       
     
     Establishment of Env-Expressing Tumor Cells and MCA205 Tumor-Rejection Assay: 
     7.5×10 5  293T cells were cotransfected with the env-expressing pDFG retroviral vector to be tested (1.75 g) and expression vectors for the MLV proteins (0.55 g for the amphotropic MLV env vector and 1.75 g for the MLV gag and pol vector). 36 hours post-transfection, supernatants were harvested for infection of MCA205 tumor cells (2.5 ml of supernatant per 5×10 5  cells with 8 μg/ml polybrene). Cells were maintained in selective medium (400 units/ml hygromycin) for 3 weeks, and then washed with PBS, trypsinized and inoculated subcutaneously in the shaved area of each mouse right flank as in Mangeney et al (1998, 2007). Tumor growth was monitored by palpation twice or thrice weekly and tumor area (mm 2 ) determined by measuring perpendicular tumor diameters. The extent of “immunosuppression” was quantified by an index based on tumor size: (A env -A none )/A none , where A env  and A none  are the mean areas at the peak of growth of tumors from Balb/c mice injected with env-expressing or control cells, respectively. 
     Analysis of HIV Env Expression: 
     293T cells were transfected with 4 mg of the expression vector for the HIV-1 envelope (pTr712) either wild-type or mutated at the indicated positions, by Calcium Phosphate precipitation. Cells are washed 16 h later and then harvested 2 days post-transfection using PBS-EDTA 5 mM. The 110-H monoclonal antibody (anti-V3 loop, gift from Hybridolab, Pasteur Institute) was used ( 1/200 dilution) to stain the HIV envelope. As a secondary antibody, the Inventors used the goat anti mouse IgG Alexa 488 ( 1/400) (Invitrogen). For intracellular HIV env staining, 293T cells were fixed with a formaldehyde buffer and then permeabilized (BD cytofix/cytoperm, BD Biosciences). The isotype mouse anti IgG1Kappa (BD Biosciences) was used to control non-specific staining. Fluorescence was acquired by flow cytometry using a FACS Calibur (BD Biosciences), and data analysed by the CellQuest software (BD Biosciences). 
     Mutated Env Pseudotyping and Measure of Viral Titer: 
     293T cells are triple transfected with 3 mg of a reporter MLV vector carrying GFP (CNCG), 1.75 mg Mo-MLV gag-pol vector and 0.55 mg phCMV vector encoding HIV-1 envelope wt or mutated at the indicated positions. The infectivity of Mo-MLV virions pseudotyped with HIV-1 Env, harvested 48 hours post-transfection, is measured using U87 cells (CD4 + , CXCR4 + ) as target cells. The infectivity of the enveloppes is analysed after 72 h exposure diluted 0.45 mm-filtered supernatant in presence of 4 mg/mL polybrene. The fluorescence (GFP) is acquired by flow cytometry using a FACS Calibur (BD Biosciences). The results are analysed by the CellQuest software (BD Biosciences). The resulting titers (number of infected cells/mL) are calculated as the following: (% GFP +  cells (infected)×plated cell number)/volume of supernatant×1000. 
     Env SIV Mutants Construction: 
     PCR fragments were generated using p239 SPE3′ (the plasmid encoding the SIV half virus containing the envelope protein) as a template and primer pairs 77-79 and 78-80, 77-81 and 78-82, 77-83 and 78-84, 77-85 and 78-86, 77-87 and 78-88, 77-89 and 78-90 to introduce the E39R, K40R, Y41R, L42R, K43R, D44R mutations respectively. The PCR products were the used as templates in subsequent PCR using primers 77-78. The resulting PCR fragment was then digested with BmgBI and NheI and inserted into the p239 SPE3′ plasmid opened with the same enzymes. 
     All the constructions were sequenced before use. 
     Introduction of SIV Mutants Ectodomain into pDFG: 
     To generate the pDFG plasmids encoding the fragment of SIV envelope ectodomain-55, PCR fragments generated using p239 SPE3′ WT and mutants as a template and primer pairs 91-92, were digested with SfiI and MluI and inserted into pDFG opened with the same enzymes. 
     
       
         
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 77 
                 Env SIV S 
                 ccgctcagtcccgaactttattggc 
                 SEQ ID NO: 350 
                   
               
               
                   
               
               
                 78 
                 Env SIV AS 
                 ggtggggaagagaacactggcc 
                 SEQ ID NO: 351 
               
               
                   
               
               
                 79 
                 SIV env E39R s 
                 cagactagggtcactgccatcCGCaagtacttaaaggaccaggcg 
                 SEQ ID NO: 352 
               
               
                   
               
               
                 80 
                 SIV env E39R as 
                 cgcctggtcctttaagtacttGCGgatggcagtgaccctagtctg 
                 SEQ ID NO: 353 
               
               
                   
               
               
                 81 
                 SIV env K40R s 
                 actagggtcactgccatcgagCGCtacttaaaggaccaggcgcag 
                 SEQ ID NO: 354 
               
               
                   
               
               
                 82 
                 SIV env K40R as 
                 ctgcgcctggtcctttaagtaGCGctcgatggcagtgaccctagt 
                 SEQ ID NO: 355 
               
               
                   
               
               
                 83 
                 SIV env Y41R s 
                 GCCATCGAGAAGcgCTTAAAGGACCAGGCG 
                 SEQ ID NO: 356 
               
               
                   
               
               
                 84 
                 SIV env Y41R as 
                 CGCCTGGTCCTTTAAGcgCTTCTCGATGGC 
                 SEQ ID NO: 357 
               
               
                   
               
               
                 85 
                 SIV env L42R s 
                 gtcactgccatcgagaagtacCGCaaggaccaggcgcagctg 
                 SEQ ID NO: 358 
               
               
                   
               
               
                 86 
                 SIV env L42R as 
                 cagctgcgcctggtccttGCGgtacttctcgatggcagtgac 
                 SEQ ID NO: 359 
               
               
                   
               
               
                 87 
                 SIV env K43R s 
                 gccatcgagaagtacttaCGCgaccaggcgcagctgaatgcttgg 
                 SEQ ID NO: 360 
               
               
                   
               
               
                 88 
                 SIV env K43R as 
                 ccaagcattcagctgcgcctggtcGCGtaagtacttctcgatggc 
                 SEQ ID NO: 361 
               
               
                   
               
               
                 89 
                 SIV env D44R s 
                 gagaagtacttaaagCGCcaggcgcagctgaatgcttgg 
                 SEQ ID NO: 362 
               
               
                   
               
               
                 90 
                 SIV env D44R as 
                 attcagctgcgcctgGCGctttaagtacttctcgatggc 
                 SEQ ID NO: 363 
               
               
                   
               
               
                 91 
                 TMSIV55 Sfi S 
                 ACATggcccagccggccgctgggatagtgcagcaac 
                 SEQ ID NO: 364 
               
               
                   
               
               
                 92 
                 TMSIV55 Mlu AS 
                 GTATacgcgtTTAaaacgcacatccccaagcattc 
                 SEQ ID NO: 365 
               
               
                   
               
             
          
         
       
     
     Comparative Example 
     Test of the In Vivo Effect of the Mutation G49R, which Corresponds to the Mutation “G19R” in the International Application WO 2010/022,740 
     WO 2010/022,740 discloses a consensus sequence of 50 amino acid of the HIV ENV protein. In this sequence, it is suggested that substitution of amino acids in positions 10, 19, 24, 34 and 40 affect the immunosuppressive properties of the HIV ENV protein. 
     These mutations are a transposition in lentivirus of the teaching of WO 2005/095,442 limited to endogenous or onco retroviruses. The authors of WO 2005/095,442 are also the authors of the present application and they early observed that such a transposition is not effective. 
     Despite the fact that any amino acids can be assigned to the positions 10, 19, 24, 34 or 40 in the consensus sequence of WO 2010/022,740, only one substitution (one residue for one position) was tested by ex vivo experiments in WO 2010/022,740. It is the mutation “G19R”, which corresponds to the mutation G49R in the present  FIGS. 1 and 3 . 
     Because the immune response of an individual involves different organs and different cellular and non-cellular components, ex vivo results have no predictive value concerning the in vivo immunosuppressive properties of a viral protein. 
     To determine if the mutations previously disclosed in WO 2010/022,740 are suitable for a medical use, the mutation G49R has been tested using the MCA205 tumor rejection in vivo assay, as defined in the section “Establishment of env-expressing tumor cells and MCA205 tumor-rejection assay” of the Example. 
     As shown in  FIG. 3 , the peptide G49R remains almost as immunosuppressive in vivo as the wild type HIV 115 peptide, with an immunosuppression index which is higher than 0.5. Thus, the mutation G49R does not induce a significant decrease of the in vivo immunosuppressive properties of the HIV ENV protein, with a ratio of immunosuppression index of G49R mutated ENV HIV 115 peptide (i mutated env )/immunosuppression index of wild type ENV HIV 115 peptide (i wild type env ), which is 0.7 (i.e. higher than 0.5). 
     This result demonstrates the insufficiently described teaching of WO 2010/022,740 since the only one mutation tested in WO 2010/022,740, using an ex vivo test, does not significantly affect the in vivo immunosuppressive properties of the HIV ENV protein. 
     As a consequence, WO 2010/022,740 raises the same technical problem as the present invention but does not offer a technical solution.