Patent Publication Number: US-2009232842-A1

Title: HPV Vaccine Comprising Peptides From Host Cell Proteins

Description:
This application is a continuation utility patent application from U.S. Utility patent application Ser. No. 11/671,095, which in turn is a continuation of international application number PCT/GB2005/002962 (publication no. WO 2006/013336) filed on Jul. 27, 2005 entitled HPV VACCINE COMPRISING PEPTIDES FROM HOST CELL PROTEINS, and claims the benefit of priority in the above-mentioned United States and international applications, and also the benefit of priority in the corresponding British national patent application no. GB 0417430.6 filed on Aug. 5, 2004 and entitled A NOVEL HPV VACCINE COMPRISING PEPTIDES FROM HOST CELL PROTEINS, the disclosures of each of which are incorporated herein in their entirety by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to a human papillomavirus (HPV) vaccine that comprises peptides from host cell proteins and more particularly, but not exclusively, to a vaccine that is directed against cancers that are associated with HPV infections, such as cervical cancer, head and neck cancer and skin cancers. The peptides comprise fragments of host cell proteins that have been targeted for degradation by HPV proteins, such as E6 and E7. Further, the invention relates to the identification of novel peptides and uses thereof. Additionally, the invention relates to novel peptide: peptide complexes and uses thereof. 
     BACKGROUND TO THE INVENTION 
     Human papillomavirus (HPV) is a very common virus that causes abnormal growth of tissue on the feet, hands, vocal cords, mouth and genital organs. Over 60 types of HPV have been identified and each type infects certain parts of the body. HPV is mainly spread through physical contact with an infected individual. In the majority of cases, HPV disappears within 1-2 years and indeed, during the course of the infection, may be subclinical; the individual may be unaware of their infection. However, in a small number of cases, HPV can progress and develop into cancer. 
     There are two kinds of abnormal tissue caused by HPV: condyloma (warts) and dysplasia (pre-cancer). Wart-like growths can be found in any infected areas and may cause itching, burning or slight bleeding. In these instances, antiviral creams may be prescribed or, in some cases, the growth may be removed or destroyed by cold cautery (freezing that destroys tissue) or hot cautery (burning warts off with an electric instrument or laser treatment). 
     Where HPV infection progresses to cancer, cancer patients are treated by a combination of surgery, radiotherapy and chemotherapy. However, radiotherapy and chemotherapy have the disadvantage of destroying healthy as well as malignant cells, and can thus cause severe side effects, while surgery is invasive and leaves the patient open to secondary infections. These side effects and risks are undesirable, and coupled to this is the fact that these treatments are not always successful, resulting in the majority of patients entering relapse and so representing with the disease. 
     It is therefore clear that more effective treatments are required, and it has been suggested that the specificity of the immune system might be harnessed against virally infected cells. This concept has been termed “immunotherapy”. 
     In particular, it has been shown that cancer patients have T cells that are capable of recognising their tumour cells, but these cells do not divide and differentiate into cytotoxic T lymphocytes (CTL) which are capable of killing these cells. 
     Cytotoxic T lymphocytes kill “target” cells, such as virally-infected cells, and have also been implicated in the “immune surveillance” of cancer cells. The majority of CTL belong to the CD8 + -subset of T cells and have T-cell receptors (TCR). These TCR are able to recognise peptides when they are expressed on the surface of cells in association with class 1 major histocompatibility complex (MHC) molecules. In man, each class of MHC is represented by more than one locus; these are called human leucocyte antigen (HLA). The class 1 HLA loci are HLA-A, -B, -C, -E, -F and -G. Additionally each HLA has different alleles and Table 1 lists those alleles that have been identified to date. 
     When a CTL encounters an antigen/MHC complex for which its TCR is specific, it enters the cell cycle and goes through several rounds of mitosis, followed by differentiation into an effector/killer cell. Differentiation includes forming a large number of modified lysosomes that contain the cell-killing proteins perforin and granzyme. Once the CTL have killed the target cells most of them will die, although a small proportion become memory cells that can respond to the antigen quickly if it reappears. 
     Tumour-reactive cytotoxic T lymphocytes have been shown to mediate tumour regression in animal models (1) and in man (2), and there has thus been an interest in using tumour-specific CTL&#39;s as an immunotherapy for human cancers. 
     In this regard monoclonal antibodies have been shown to be effective against some cancers, especially cancers of white blood cells, and are targeted at a molecule or receptor that is associated with cancer cells. Table 2 lists some of these antibodies and their mechanism of action. 
     Alternatively, dendritic-cell vaccines have been used to elicit a tumour-specific CTL response. Dendritic cells are the most potent antigen-presenting cells and they act by engulfing antigen, processing it into peptides and presenting it to T cells. To make a dendritic-cell vaccine, dendritic cells are harvested, exposed in vitro to antigen associated with the type of tumour in the patient, and then re-injected into the patient. To date these vaccines have shown some promise against melanoma, prostrate cancer and lymphoma. 
     Ideally these vaccines target molecules that are expressed on cancer cells, but not on healthy cells. However such tumour-specific antigens have been hard to find, and as a result many of the immune agents now in use also target healthy cells in the hope that these cells, eventually, will be replaced. As with radiotherapy and chemotherapy, this treatment can cause severe side effects and also leads to the potential for autoimmunity (3). Indeed, in the case of a telomerase vaccine, this protein is also present in the stem cells of bone marrow, reproductive organs and perhaps other tissues. Further, the antigen to which some dendritic cells are exposed include tyrosinase, which is to be found in melanocytes, or prostatic acid phosphatase (PAP), which is to be found in prostate cells. 
     It is therefore clear that additional viral therapies are needed, particularly for those patients with an advanced stage disease that has failed to respond to conventional viral or cancer treatments. 
     Recently, a number of studies have shown that high-level expression of certain proteins in tumour cells is sufficient to allow CTL to discriminate between tumours and normal cells (4,5). 
     One way of avoiding autoimmunity in tumour immunotherapy is to target the 15% of human malignancies that are associated with viruses. Of these the strongest association is between cervical cancer and human papillomarivus, with 99.7% of cervical cancers containing HPV DNA (6). There are over 25 HPVs that infect the genital mucosa and give rise to malignancies such as cervical cancer, head and neck cancers and skin cancers. These “high risk” HPVs are characterised by at least two oncogene products: E6 and E7, which act to immortalise and transform, in the cervix, epithelial cells. The expression of these proteins is thought to be essential to retain the transformed phenotype of the cancer cell and so these non-self viral proteins are therefore attractive targets for CTL mediated immunotherapy. 
     CTL active against HPV E6/E7 can be induced by vaccination (7) and such CTL have been detected with variable frequency in patients with premalignant cervical disease (8) or cancer (9). However it has been difficult to generate these CTL in vitro, probably because they occur at low frequency (10). A major limitation of using these proteins as tumour-specific targets is that they are expressed at low levels in cancer cells (11). Furthermore, the E6 and E7 proteins themselves are small and contain few epitopes suitable for recognition by CTL (12). 
     The present invention aims to overcome these problems by identifying and then targeting peptides that are recognised by CTL, which peptides are specific to HPV transformed cells and are very unlikely to give rise to autoimmunity. These peptides are either uniquely presented or over-presented in HPV transformed cells, and the proteins from which these peptides are derived are, typically, either absent or appear to be expressed at very low levels in HPV transformed cells. In contrast, these proteins occur at normal or high levels in normal cells. 
     The invention is based on the mechanism that HPV E6 and E7 oncoproteins use to mediate targeted degradation of host cell proteins such as retinoblastoma proteins (Rb), C-MYC and HMCM7, among others (see Table 3), which takes place during transformation of the infected cell. 
     It is well known that HPV oncoproteins bind to and facilitate the degradation of host cell proteins, such as Rb. Thus, analysis of HPV transformed cervical carcinomas reveals no apparent expression of full-length Rb protein, whereas normal cells have high cellular levels of the Rb protein, as this is not normally proteolytically degraded (13). 
     It has been shown that Rb proteins are degraded by the ubiquitin-dependant proteolysis system (13), and more recently, it has come to light that intracellular organelles called proteasomes play a role in mediating degradation (18,19) of host cell proteins after interaction with E6 or E7 oncoproteins. 
     We have recognised the fact that the degradation of, for example ubiquinated protein substrates by proteasomes, is possibly the major mechanism by which peptides recognised by CTL&#39;s are generated (20, 21). For example, in a virally infected cell, newly synthesised viral proteins in the cytoplasm are degraded by proteasomes into peptide fragments. These peptides are transported into the endoplasmic reticulum (ER) by transporter associated with antigen processing (TAP) proteins. Once inside the ER, the peptides will bind to free MHC class I molecules and beta 2 microglobulin to form a mature MHC/peptide complex. This is transported to the cell surface where it may be recognised by CTL.  FIG. 1  shows a diagrammatic representation of this process. 
     Accordingly, the present invention is based on the theory that in HPV transformed cells, Rb proteins (and other proteins, see Table 3) will be targeted for degradation, processed and peptides thereof will be presented on the surface of the cell as peptides that can be recognised by CTL. In non-HPV transformed, or normal, cells these proteins will not be degraded significantly, so these peptides, effectively, will not be available for CTL recognition. Thus, HPV transformed cells should have high levels of, for example, Rb derived peptides typically co-presented on the cell surface in a peptide HLA complex, but low intracellular levels of the full-length proteins, contrary to normal cells ( FIG. 2 ). 
     The use of host cell proteins as targets for immunotherapy is not novel. However, in all previous instances this approach has relied on the over-expression of proteins in tumours, compared to normal cells. For example, host cell proteins such as p53 (5), Wilms transcription factor (WT1), Her 21Neu (16) and hTert (17) have been proposed as “tumour-specific” antigens, as all of these are over-expressed in tumour cells. To our knowledge, this is the first time that a HPV or cancer vaccine has been directed at “tumour-specific” proteins, and more particularly peptides thereof, that are expressed at normal, low, or undetectable levels in HPV transformed cells, compared to normal cells. 
     Previously, high levels of antigen expression were thought advantageous in order to allow CTL to discriminate between tumour cells and normal cells. 
     Additionally, up until now HPV vaccines have comprised proteins that are produced by HPV, not host proteins that are targeted for degradation by this virus. 
     In summary, the current invention relies on a relatively high level of presentation of peptides at the cell surface but not necessarily on relatively high levels of expression, or apparent expression, of the corresponding proteins in the virally-infected cell. In fact, low level or no expression of the tumour-specific protein would typically indicate that the protein was being targeted for degradation by viral proteins and so was present at low intracellular levels, but following degradation, presented at the cell membrane and so was available as a peptide for CTL recognition. 
     Accordingly, in one aspect of the invention, there is therefore provided a vaccine comprising: at least one isolated, purified, synthesised or recombinant peptide, wherein the peptide is a fragment of a host cell protein that has been degraded by human papillomavirus oncoproteins, and can elicit a CTL response when administered to a mammal. 
     Reference herein to a cell protein that has been degraded by human papillomavirus oncoproteins includes reference to a protein that has been selectively targeted for degradation by HPV oncoproteins and so includes a protein that, in a HPV transformed cell, would be selectively targeted for degradation or a protein that is acted upon by human HPV oncoproteins in such a way that it is, directly or indirectly, degraded, most typically but not exclusively, by the ubiquitin pathway. 
     In a preferred embodiment of the invention the mammal is human. 
     Preferably, the oncoprotein is E6 or E7. 
     The host cell protein may be any protein that is degraded by viral proteins, such as E6 or E7, and Table 3 lists those proteins that are currently known to be targeted for degradation by E6 or E7. 
     Preferably, the peptide is HPV-specific or tumour-specific, meaning that it is presented in high amounts on the cell surface of HPV transformed or tumour cells, relative to normal cells. 
     Even more preferably, the peptide is 9 to 30 amino acids in length. 
     Alternatively, the peptide may be 9 to 11 amino acids in length. 
     The CTL response is preferably a HPV-specific or tumour-specific CTL response, meaning that the CTL can recognise HPV transformed cells or tumour cells expressing the peptides of the vaccine. 
     More preferably, the vaccine comprises one or more of the peptides shown in Table 4 (SEQ ID NOS: 1-163). 
     More preferably still, the vaccine comprises any of the aforementioned peptides plus a further protein or peptide comprising a major histocompatability complex molecule, ideally, a class I molecule and more specifically a human leucocyte antigen (HLA), and more ideally still a HLA selected from Table 1. 
     In another aspect of the invention, there is provided a vaccine comprising: at least one isolated, purified, synthesised or recombinant peptide, wherein the peptide is chosen from those listed in Table 4. 
     In yet another aspect of the invention, there is provided a vaccine comprising: at least one isolated, purified, synthesised or recombinant peptide selected from Table 4 and, further at least one isolated, purified, synthesised or recombinant HLA selected from those listed in Table 1. 
     In a further aspect of the invention, there is provided a vaccine comprising: at least one isolated, purified, synthesised or recombinant nucleic acid molecule encoding any peptide or peptide/HLA complex as described above. 
     In this embodiment, the nucleic acid molecule may be in the form of a vector that comprises a recombinant construct. Ideally the construct is adapted for the expression of said vaccine in a selected host system. The host system is a cell, plasmid, virus, live organism or other similar vehicle. 
     According to a further aspect of the invention there is provided a host cell transformed or transfected with the vector of the invention. 
     Additionally, the present invention provides a method of manufacturing a vaccine, which method comprises; culturing a host cell transformed or transfected with a vector comprising a recombinant construct as described above; and isolating/purifying the resulting construct product. 
     The peptides of the present invention may also be used to generate and isolate HPV-specific or tumour-specific cytotoxic T lymphocytes or their T cell receptors or the genes encoding said receptors, in vitro, for use in adoptive immunotherapy. This could for example be carried out by culturing T lymphocytes with at least one of the peptides described above. 
     According to yet a further aspect of the invention there is provided a method of identifying HPV-specific or tumour-specific cytotoxic T lymphocytes comprising: 
     (a) culturing a sample containing cytotoxic T lymphocytes with at least one peptide that represents a fragment of a host cell protein which is degraded by HPV proteins when said host cell is transformed or transfected by HPV whereby said peptide is ultimately presented on a surface of a virally infected cell; and
 
(b) selecting CTL that recognise said peptide by binding thereto.
 
     In a preferred method of the invention said peptide is one selected from the list shown in Table 4. In yet a further preferred method of the invention the CTL are CD8 +  cells. 
     It will be apparent to those skilled in the art that CTL receptors may further be identified using the aforementioned method. 
     The present invention can be used to treat HPV associated diseases and particularly cancer, preferably cervical cancer, head and neck squamous cell cancer, non-melanoma skin cancers, liver cancer, mesothioloma or prostrate cancer. 
     Furthermore, the present invention also provides a method of treatment, which method comprises administering a vaccine as described above, to a mammal to be treated. Ideally, the mammal is human. 
     According to a further aspect of the invention there is provided a peptide, or a nucleic acid molecule encoding same, selected from the list shown in Table 4. 
     In a further embodiment of the invention, said peptide is for use as a vaccine and in particular for use as a HPV vaccine to treat HPV associated disorders. 
     According to a further aspect of the invention there is provided a complex comprising at least one of the peptides listed in Table 4 in association with a HLA co-presenting peptide. 
     More preferably the HLA peptide is one of the peptides listed in Table 1 and more specifically HLA-A binding protein and more specifically still HLA-A 0201. 
     According to a further aspect of the invention there is provided the use of a HPV-specific peptide for the production of a HPV vaccine wherein said peptide is a fragment of a mammalian cell protein that has been degraded by human papillomavirus oncoproteins and which is presented, in combination with HLA, at the surface of the transformed or transfected HPV cell whereby the recognition of this peptide HLA complex by a cytotoxic T lymphocyte results in the elicitation of an immune response. 
    
    
     
       The invention will now be described by way of the following examples and with reference to the following Figures wherein: 
         FIG. 1  shows a mechanism for T cell recognition of host cell proteins in cells transformed by human papillomavirus; 
         FIG. 2  shows a difference in presentation of host cell peptides in normal and HPV transformed cells; 
         FIG. 3  shows HLA-A2 binding of host protein derived peptides. Specifically, HLA-A*0201 expression of T2 cells was monitored by flow cytometry after overnight incubation with 100 μg test peptides. Each peptide was tested in quadruplicate. A % increase in HLA-A*0201 expression of above 50% was considered significant; 
         FIG. 4  shows generation of T cell responses in vivo against a peptide derived from human Rb protein. Specifically, HLA-A2/Kb transgenic mice were immunised with 100 μg of test peptide emulsified in incomplete freunds adjuvant. Two to four mice were tested for each peptide. Ten to eleven days later, mice were sacrificed and splenocytes tested in ELISPOT assays. These measured the numbers of IFN −  producing T cells (spots) specific for the immunising peptide. Positive results were confirmed in at least two further repeat experiments. Representative data from 1 experiment testing M1 58-66 , Rb1, Rb7 and BAK18 peptides, are shown; 
         FIG. 5  shows CD8 +  T cells recognising Rb7 can be detected in healthy HLA-A2 +  donors. Specifically, CD8+ T cells were cultured with Rb7 (panels C&amp;D) or Melan-A/Mart1 26-35  (panels A&amp;B) peptides for 14 days On day 0 and day 14 days, the numbers of peptide specific CD8 +  T cells were measured using appropriate fluoresceinated peptide:HLA-A2 pentamers. These were analysed on a flow cytometer and expressed as % of gated cells, excluding dead and CD14 +  cells. Results for donor 5 (from table 4) are shown; and 
         FIG. 6  shows functional CD8 +  T cells recognising Rb7 can be detected in healthy donors. Specifically, peripheral blood lymphocytes from HLA-A2 +  healthy donors were enriched for CD8+ T cells, then cultured for 14 days with Rb7 peptide and antigen presenting cells (APC). The cultured cells were harvested and tested in enzyme linked immunospot (ELISPOT) assays to measure the numbers of T cells able to secrete IFN—in response to Rb7 peptide. Three (A, B, C) out of seven donors were capable of making significant responses (number of spots for T cells+Rb7+PBMC &gt;2 standard deviations above T cells+PBMC). 
     
    
    
     EXAMPLE 1 
     Candidate 9 or 10 amino acid peptides from 15 proteins were selected for analysis, see Table 4 for the full list of peptides. One hundred and two peptides predicted to bind to HLA-A*0201 were selected according to published algorithms (33,34). (Table 4). The algorithm we used has been used previously to successfully predict other tumour-specific CTL epitopes (17). We chose HLA-A*0201 as the co-presenting peptide as this is the most common HLA allele (˜40%) among Caucasians, and there are well-defined in vivo and in vitro model systems to facilitate proof of concept experiments. From the initial list of 102 peptides, 62 were synthesized for testing. 
     Peptides were Tested for Binding to HLA-A*0201. 
     CTL recognise peptides bound to HLA class I molecules on the cell surface. Therefore peptides must demonstrate binding to HLA to be useful. This can be measured by using a cell based assay measuring an increase in HLA-A*0201 expression resulting from binding. 
     A cell-based peptide binding assay ((35)) was used to show that the majority (43162) of candidate peptides could bind to HLA-A*0201 (Table 3  FIG. 3 ). 
     HLA-A2 Binding of Host Protein Derived Peptides. 
     HLA-A*0201 expression of T2 cells was monitored by flow cytometry after overnight incubation with 100 μg test peptides. Each peptide was tested in quadruplicate. A percentage increase in HLA-A*0201 expression of above 50% was considered significant. 
     The level of binding observed could be classified as either strong or moderate, and was comparable to two well-known HLA-A*0201 restricted CTL epitopes (influenza M1 and EBV BMFL1)( FIG. 3 ). 
     43 of the peptides that showed a greater than 50% increase in HLA-A*0201 expression were chosen as candidates for testing in immunogenicity experiments. 
     Testing In Vivo Immunogenicity in Mice. 
     We have used HLA-A*0201 transgenic mice to test potential human vaccines (36). These mice can be immunised with peptides together with adjuvant to monitor development of in vivo responses. These responses were detected using ELISPOT assays to measure the numbers of IFN-γ securing peptide specific T cells in the spleen. 
     This was done with 20 peptides from the Rb(6), Muppl (7), BAK (3), DLG (2), AP (2) proteins. All peptides were chosen on the strength of peptide binding ( FIG. 3 ). The M1 58-66  peptide from influenza, a known HLA-A*0201 binder was used as a positive control. Significant T cell responses were seen against the positive control M1 58-66  peptide (7/12 mice) and a peptide from Rb 485-493  (Rb7) protein (7/10 mice). The results are shown in  FIG. 4 . 
     Testing In Vitro Immunogenicity using Human T Lymphocytes. 
     The candidate peptides must be capable of activating human T lymphocytes that can recognise and kill cancer cells. We detected peptide specific T cells in the peripheral blood of patients with cervical cancer. This proved the concept that such peptides can be immunogenic despite being derived from “self” proteins. 
     Detection of Peptide Specific T Cells 
     T cells reactive against peptides of the invention should be preferentially found in HLA-A2 +  patients with cervical cancer. Blood samples from 4 patients (3 with cervical cancer, 1 with premalignant disease, CIN3) were tested for the presence of CD8 +  T cells recognising Rb7 peptide. Fluoresceinated multimeric HLA-A2/peptide complexes were used to measure numbers of peptide specific T cells by flow cytometry (10). This assay demonstrated that T cells specific for Rb7 peptide could be detected at low frequency in the blood of 2 patients with cervical cancer. These frequencies were similar to those previously obtained for HPV16 E7 peptide specific T cells (10). This suggests that it should be possible to isolate and propagate Rb specific T cells for further experiments. 
     Using the technique described above, T lymphocytes recognising certain “self” tumour antigens such as melan-A can also be readily detected in healthy donors (50). However it is usually the case that T lymphocytes recognising “self” antigens are difficult to detect in healthy donors. Blood samples from 8 healthy donors (all HLA-A2+) were tested for the presence of CD8 +  T cells recognising Rb7 peptide and melan-A peptide, using appropriate fluoresceinated multimers (pentamers). T lymphocytes recognising Rb7 peptide could be detected at variable but generally low frequencies in all 8 healthy donors (Table 6). By contrast T lymphocyte responses against melan-A were extremely high frequency, confirming previous reports (50). The highest frequency of T lymphocytes specific for Rb7 was found in donor 5 ( FIG. 5 ). 
     The assays described above demonstrate that human T cells recognising Rb7 can be detected in both patients and healthy donors. ELISPOT assays were used to determine whether Rb7 peptide specific CD8 +  T lymphocytes cultured from healthy donors, were capable of secreting IFN-γ. Seven healthy donors were tested, with 3 donors demonstrating detectable numbers of IFN-γ secreting T lymphocytes ( FIG. 5 ). 
     Overall these results suggest that host cell protein fragments produced by HPV processing, such as the Rb7 peptide, is immunogenic for human CD8 +  T lymphocytes, and can elicit functional (IFN-γ secretion) responses. This suggests that it should be possible to isolate and propagate large numbers of Rb specific T cells for either experimental or clinical therapeutic use. 
     
       
         
           
               
            
               
                   
               
               
                 Full List of HLA Class I alleles assigned as of July 2005 
               
            
           
           
               
               
               
               
               
               
            
               
                 HLA-A 
                 HLA-B 
                 HLA-C 
                 HLA-E 
                 HLA-F 
                 HLA-G 
               
               
                   
               
               
                 A*01010101 
                 B*070201 
                 Cw*010201 
                 E*01010101 
                 F*010101 
                 G*010101 
               
               
                 A*01010102N 
                 B*070202 
                 Cw*010202 
                 E*01010102 
                 F*010102 
                 G*010102 
               
               
                 A*010102 
                 B*070203 
                 Cw*010203 
                 E*01030101 
                   
                 G*010103 
               
               
                 A*010103 
                 B*070204 
                 Cw*0103 
                 E*01030102 
                   
                 G*010104 
               
               
                 A*0102 
                 B*0703 
                 Cw*0104 
                 E*010302 
                   
                 G*010105 
               
               
                 A*0103 
                 B*0704 
                 Cw*0105 
                 E*010303 
                   
                 G*010106 
               
               
                 A*0104N 
                 B*0705 
                 Cw*0106 
                 E*010304 
                   
                 G*010107 
               
               
                 A*0106 
                 B*0706 
                 Cw*0107 
                 E*0104 
                   
                 G*010108 
               
               
                 A*0107 
                 B*0707 
                 Cw*0108 
                   
                   
                 G*0102 
               
               
                 A*0108 
                 B*0708 
                 Cw*0109 
                   
                   
                 G*0103 
               
               
                 A*0109 
                 B*0709 
                 Cw*0110 
                   
                   
                 G*010401 
               
               
                 A*0110 
                 B*0710 
                 Cw*0111 
                   
                   
                 G*010402 
               
               
                 A*0111N 
                 B*0711 
                 Cw*020201 
                   
                   
                 G*010403 
               
               
                 A*0112 
                 B*0712 
                 Cw*020202 
                   
                   
                 G*0105N 
               
               
                 A*0113 
                 B*0713 
                 Cw*020203 
                   
                   
                 G*0106 
               
               
                 A*0114 
                 B*0714 
                 Cw*020204 
               
               
                 A*0115N 
                 B*0715 
                 Cw*020205 
               
               
                 A*02010101 
                 B*0716 
                 Cw*0203 
               
               
                 A*02010102L 
                 B*0717 
                 Cw*0204 
               
               
                 A*020102 
                 B*0718 
                 Cw*0205 
               
               
                 A*020103 
                 B*0719 
                 Cw*0206 
               
               
                 A*020104 
                 B*0720 
                 Cw*0207 
               
               
                 A*020105 
                 B*0721 
                 Cw*0208 
               
               
                 A*020106 
                 B*0722 
                 Cw*0209 
               
               
                 A*020107 
                 B*0723 
                 Cw*0210 
               
               
                 A*020108 
                 B*0724 
                 Cw*0211 
               
               
                 A*020109 
                 B*0725 
                 Cw*0212 
               
               
                 A*020110 
                 B*0726 
                 Cw*030201 
               
               
                 A*020111 
                 B*0727 
                 Cw*030202 
               
               
                 A*0202 
                 B*0728 
                 Cw*030301 
               
               
                 A*020301 
                 B*0729 
                 Cw*030302 
               
               
                 A*020302 
                 B*0730 
                 Cw*030303 
               
               
                 A*0204 
                 B*0731 
                 Cw*030304 
               
               
                 A*0205 
                 B*0732 
                 Cw*030401 
               
               
                 A*020601 
                 B*0733 
                 Cw*030402 
               
               
                 A*020602 
                 B*0734 
                 Cw*030403 
               
               
                 A*020603 
                 B*0735 
                 Cw*0305 
               
               
                 A*0207 
                 B*0736 
                 Cw*0306 
               
               
                 A*0208 
                 B*0737 
                 Cw*0307 
               
               
                 A*0209 
                 B*0738 
                 Cw*0308 
               
               
                 A*0210 
                 B*0739 
                 Cw*0309 
               
               
                 A*0211 
                 B*0740 
                 Cw*0310 
               
               
                 A*0212 
                 B*0741 
                 Cw*0311 
               
               
                 A*0213 
                 B*0742 
                 Cw*0312 
               
               
                 A*0214 
                 B*0743 
                 Cw*0313 
               
               
                 A*0215N 
                 B*080101 
                 Cw*0314 
               
               
                 A*0216 
                 B*080102 
                 Cw*0315 
               
               
                 A*021701 
                 B*0802 
                 Cw*0316 
               
               
                 A*021702 
                 B*0803 
                 Cw*0317 
               
               
                 A*0218 
                 B*0804 
                 Cw*0318 
               
               
                 A*0219 
                 B*0805 
                 Cw*0319 
               
               
                 A*022001 
                 B*0806 
                 Cw*04010101 
               
               
                 A*022002 
                 B*0807 
                 Cw*04010102 
               
               
                 A*0221 
                 B*0808N 
                 Cw*040102 
               
               
                 A*0222 
                 B*0809 
                 Cw*040103 
               
               
                 A*0224 
                 B*0810 
                 Cw*0403 
               
               
                 A*0225 
                 B*0811 
                 Cw*040401 
               
               
                 A*0226 
                 B*0812 
                 Cw*040402 
               
               
                 A*0227 
                 B*0813 
                 Cw*0405 
               
               
                 A*0228 
                 B*0814 
                 Cw*0406 
               
               
                 A*0229 
                 B*0815 
                 Cw*0407 
               
               
                 A*0230 
                 B*0816 
                 Cw*0408 
               
               
                 A*0231 
                 B*0817 
                 Cw*0409N 
               
               
                 A*0232N 
                 B*0818 
                 Cw*0410 
               
               
                 A*0233 
                 B*0819N 
                 Cw*0411 
               
               
                 A*0234 
                 B*0820 
                 Cw*0412 
               
               
                 A*023501 
                 B*0821 
                 Cw*0413 
               
               
                 A*023502 
                 B*0822 
                 Cw*0414 
               
               
                 A*0236 
                 B*0823 
                 Cw*0415 
               
               
                 A*0237 
                 B*0824 
                 Cw*0416 
               
               
                 A*0238 
                 B*0825 
                 Cw*0417 
               
               
                 A*0239 
                 B*1301 
                 Cw*050101 
               
               
                 A*0240 
                 B*130201 
                 Cw*050102 
               
               
                 A*0241 
                 B*130202 
                 Cw*0502 
               
               
                 A*0242 
                 B*1303 
                 Cw*0503 
               
               
                 A*0243N 
                 B*1304 
                 Cw*0504 
               
               
                 A*0244 
                 B*1306 
                 Cw*0505 
               
               
                 A*0245 
                 B*1307N 
                 Cw*0506 
               
               
                 A*0246 
                 B*1308 
                 Cw*0507N 
               
               
                 A*0247 
                 B*1309 
                 Cw*0508 
               
               
                 A*0248 
                 B*1310 
                 Cw*0509 
               
               
                 A*0249 
                 B*1311 
                 Cw*0510 
               
               
                 A*0250 
                 B*1312 
                 Cw*0511 
               
               
                 A*0251 
                 B*1313 
                 Cw*0602 
               
               
                 A*0252 
                 B*1401 
                 Cw*0603 
               
               
                 A*0253N 
                 B*140201 
                 Cw*0604 
               
               
                 A*0254 
                 B*140202 
                 Cw*0605 
               
               
                 A*0255 
                 B*1403 
                 Cw*0606 
               
               
                 A*0256 
                 B*1404 
                 Cw*0607 
               
               
                 A*0257 
                 B*1405 
                 Cw*0608 
               
               
                 A*0258 
                 B*140601 
                 Cw*0609 
               
               
                 A*0259 
                 B*140602 
                 Cw*0610 
               
               
                 A*0260 
                 B*1407N 
                 Cw*0611 
               
               
                 A*0261 
                 B*15010101 
                 Cw*0612 
               
               
                 A*0262 
                 B*15010102N 
                 Cw*0613 
               
               
                 A*0263 
                 B*150102 
                 Cw*070101 
               
               
                 A*0264 
                 B*150103 
                 Cw*070102 
               
               
                 A*0265 
                 B*150104 
                 Cw*070103 
               
               
                 A*0266 
                 B*150105 
                 Cw*07020101 
               
               
                 A*0267 
                 B*1502 
                 Cw*07020102 
               
               
                 A*0268 
                 B*1503 
                 Cw*07020103 
               
               
                 A*0269 
                 B*1504 
                 Cw*0703 
               
               
                 A*0270 
                 B*1505 
                 Cw*070401 
               
               
                 A*0271 
                 B*1506 
                 Cw*070402 
               
               
                 A*0272 
                 B*1507 
                 Cw*0705 
               
               
                 A*0273 
                 B*1508 
                 Cw*0706 
               
               
                 A*027401 
                 B*1509 
                 Cw*0707 
               
               
                 A*027402 
                 B*1510 
                 Cw*0708 
               
               
                 A*0275 
                 B*151101 
                 Cw*0709 
               
               
                 A*0276 
                 B*151102 
                 Cw*0710 
               
               
                 A*0277 
                 B*1512 
                 Cw*0711 
               
               
                 A*0278 
                 B*1513 
                 Cw*0712 
               
               
                 A*0279 
                 B*1514 
                 Cw*0713 
               
               
                 A*0280 
                 B*1515 
                 Cw*0714 
               
               
                 A*0281 
                 B*1516 
                 Cw*0715 
               
               
                 A*0282N 
                 B*15170101 
                 Cw*0716 
               
               
                 A*0283N 
                 B*15170102 
                 Cw*0717 
               
               
                 A*0284 
                 B*151702 
                 Cw*0718 
               
               
                 A*0285 
                 B*1518 
                 Cw*0719 
               
               
                 A*0286 
                 B*1519 
                 Cw*0720 
               
               
                 A*03010101 
                 B*1520 
                 Cw*0721 
               
               
                 A*03010102N 
                 B*1521 
                 Cw*0722 
               
               
                 A*03010103 
                 B*1523 
                 Cw*0723 
               
               
                 A*030102 
                 B*1524 
                 Cw*0724 
               
               
                 A*030103 
                 B*1525 
                 Cw*0725 
               
               
                 A*030104 
                 B*1526N 
                 Cw*0726 
               
               
                 A*0302 
                 B*1527 
                 Cw*0727 
               
               
                 A*0303N 
                 B*1528 
                 Cw*0728 
               
               
                 A*0304 
                 B*1529 
                 Cw*0729 
               
               
                 A*0305 
                 B*1530 
                 Cw*0730 
               
               
                 A*0306 
                 B*1531 
                 Cw*080101 
               
               
                 A*0307 
                 B*1532 
                 Cw*080102 
               
               
                 A*0308 
                 B*1533 
                 Cw*0802 
               
               
                 A*0309 
                 B*1534 
                 Cw*0803 
               
               
                 A*0310 
                 B*1535 
                 Cw*0804 
               
               
                 A*0311N 
                 B*1536 
                 Cw*0805 
               
               
                 A*0312 
                 B*1537 
                 Cw*0806 
               
               
                 A*0313 
                 B*1538 
                 Cw*0807 
               
               
                 A*0314 
                 B*1539 
                 Cw*0808 
               
               
                 A*0315 
                 B*1540 
                 Cw*0809 
               
               
                 A*0316 
                 B*1542 
                 Cw*0810 
               
               
                 A*0317 
                 B*1543 
                 Cw*0811 
               
               
                 A*110101 
                 B*1544 
                 Cw*0812 
               
               
                 A*110102 
                 B*1545 
                 Cw*120201 
               
               
                 A*110103 
                 B*1546 
                 Cw*120202 
               
               
                 A*110104 
                 B*1547 
                 Cw*120203 
               
               
                 A*110105 
                 B*1548 
                 Cw*120301 
               
               
                 A*1102 
                 B*1549 
                 Cw*120302 
               
               
                 A*1103 
                 B*1550 
                 Cw*120303 
               
               
                 A*1104 
                 B*1551 
                 Cw*120401 
               
               
                 A*1105 
                 B*1552 
                 Cw*120402 
               
               
                 A*1106 
                 B*1553 
                 Cw*1205 
               
               
                 A*1107 
                 B*1554 
                 Cw*1206 
               
               
                 A*1108 
                 B*1555 
                 Cw*1207 
               
               
                 A*1109 
                 B*1556 
                 Cw*1208 
               
               
                 A*1110 
                 B*1557 
                 Cw*1209 
               
               
                 A*1111 
                 B*1558 
                 Cw*1210 
               
               
                 A*1112 
                 B*1560 
                 Cw*1211 
               
               
                 A*1113 
                 B*1561 
                 Cw*1212 
               
               
                 A*1114 
                 B*1562 
                 Cw*1213 
               
               
                 A*1115 
                 B*1563 
                 Cw*1214 
               
               
                 A*1116 
                 B*1564 
                 Cw*1215 
               
               
                 A*1117 
                 B*1565 
                 Cw*140201 
               
               
                 A*1118 
                 B*1566 
                 Cw*140202 
               
               
                 A*1119 
                 B*1567 
                 Cw*140203 
               
               
                 A*1120 
                 B*1568 
                 Cw*140204 
               
               
                 A*1121N 
                 B*1569 
                 Cw*1403 
               
               
                 A*1122 
                 B*1570 
                 Cw*1404 
               
               
                 A*1123 
                 B*1571 
                 Cw*1405 
               
               
                 A*2301 
                 B*1572 
                 Cw*1406 
               
               
                 A*2302 
                 B*1573 
                 Cw*1407N 
               
               
                 A*2303 
                 B*1574 
                 Cw*150201 
               
               
                 A*2304 
                 B*1575 
                 Cw*150202 
               
               
                 A*2305 
                 B*1576 
                 Cw*1503 
               
               
                 A*2306 
                 B*1577 
                 Cw*1504 
               
               
                 A*2307N 
                 B*1578 
                 Cw*150501 
               
               
                 A*2308N 
                 B*1579N 
                 Cw*150502 
               
               
                 A*2309 
                 B*1580 
                 Cw*150503 
               
               
                 A*2310 
                 B*1581 
                 Cw*150504 
               
               
                 A*2311N 
                 B*1582 
                 Cw*1506 
               
               
                 A*2312 
                 B*1583 
                 Cw*1507 
               
               
                 A*24020101 
                 B*1584 
                 Cw*1508 
               
               
                 A*24020102L 
                 B*1585 
                 Cw*1509 
               
               
                 A*240202 
                 B*1586 
                 Cw*1510 
               
               
                 A*240203 
                 B*1587 
                 Cw*1511 
               
               
                 A*240204 
                 B*1588 
                 Cw*1512 
               
               
                 A*240205 
                 B*1589 
                 Cw*1513 
               
               
                 A*240206 
                 B*1590 
                 Cw*1514 
               
               
                 A*240301 
                 B*1591 
                 Cw*160101 
               
               
                 A*240302 
                 B*1592 
                 Cw*160102 
               
               
                 A*2404 
                 B*1593 
                 Cw*1602 
               
               
                 A*2405 
                 B*1594N 
                 Cw*160401 
               
               
                 A*2406 
                 B*1595 
                 Cw*1606 
               
               
                 A*2407 
                 B*1596 
                 Cw*1607 
               
               
                 A*2408 
                 B*1597 
                 Cw*1701 
               
               
                 A*2409N 
                 B*1598 
                 Cw*1702 
               
               
                 A*2410 
                 B*1599 
                 Cw*1703 
               
               
                 A*2411N 
                 B*180101 
                 Cw*1801 
               
               
                 A*2413 
                 B*180102 
                 Cw*1802 
               
               
                 A*2414 
                 B*1802 
               
               
                 A*2415 
                 B*1803 
               
               
                 A*2417 
                 B*1804 
               
               
                 A*2418 
                 B*1805 
               
               
                 A*2419 
                 B*1806 
               
               
                 A*2420 
                 B*1807 
               
               
                 A*2421 
                 B*1808 
               
               
                 A*2422 
                 B*1809 
               
               
                 A*2423 
                 B*1810 
               
               
                 A*2424 
                 B*1811 
               
               
                 A*2425 
                 B*1812 
               
               
                 A*2426 
                 B*1813 
               
               
                 A*2427 
                 B*1814 
               
               
                 A*2428 
                 B*1815 
               
               
                 A*2429 
                 B*1817N 
               
               
                 A*2430 
                 B*1818 
               
               
                 A*2431 
                 B*1819 
               
               
                 A*2432 
                 B*1820 
               
               
                 A*2433 
                 B*2701 
               
               
                 A*2434 
                 B*2702 
               
               
                 A*2435 
                 B*2703 
               
               
                 A*2436N 
                 B*270401 
               
               
                 A*2437 
                 B*270402 
               
               
                 A*2438 
                 B*270502 
               
               
                 A*2439 
                 B*270503 
               
               
                 A*2440N 
                 B*270504 
               
               
                 A*2441 
                 B*270505 
               
               
                 A*2442 
                 B*270506 
               
               
                 A*2443 
                 B*270507 
               
               
                 A*2444 
                 B*270508 
               
               
                 A*2445N 
                 B*270509 
               
               
                 A*2446 
                 B*2706 
               
               
                 A*2447 
                 B*2707 
               
               
                 A*2448N 
                 B*2708 
               
               
                 A*2449 
                 B*2709 
               
               
                 A*2450 
                 B*2710 
               
               
                 A*2451 
                 B*2711 
               
               
                 A*2452 
                 B*2712 
               
               
                 A*2453 
                 B*2713 
               
               
                 A*250101 
                 B*2714 
               
               
                 A*250102 
                 B*2715 
               
               
                 A*2502 
                 B*2716 
               
               
                 A*2503 
                 B*2717 
               
               
                 A*2504 
                 B*2718 
               
               
                 A*260101 
                 B*2719 
               
               
                 A*260102 
                 B*2720 
               
               
                 A*260103 
                 B*2721 
               
               
                 A*260104 
                 B*2723 
               
               
                 A*2602 
                 B*2724 
               
               
                 A*2603 
                 B*2725 
               
               
                 A*2604 
                 B*2726 
               
               
                 A*2605 
                 B*2727 
               
               
                 A*2606 
                 B*2728 
               
               
                 A*260701 
                 B*2729 
               
               
                 A*260702 
                 B*2730 
               
               
                 A*2608 
                 B*350101 
               
               
                 A*2609 
                 B*350102 
               
               
                 A*2610 
                 B*350103 
               
               
                 A*2611N 
                 B*350104 
               
               
                 A*2612 
                 B*350201 
               
               
                 A*2613 
                 B*350202 
               
               
                 A*2614 
                 B*3503 
               
               
                 A*2615 
                 B*350401 
               
               
                 A*2616 
                 B*350402 
               
               
                 A*2617 
                 B*3505 
               
               
                 A*2618 
                 B*3506 
               
               
                 A*2619 
                 B*3507 
               
               
                 A*2620 
                 B*3508 
               
               
                 A*2621 
                 B*350901 
               
               
                 A*2622 
                 B*350902 
               
               
                 A*2623 
                 B*3510 
               
               
                 A*2624 
                 B*3511 
               
               
                 A*2625N 
                 B*3512 
               
               
                 A*2626 
                 B*3513 
               
               
                 A*29010101 
                 B*351401 
               
               
                 A*29010102N 
                 B*351402 
               
               
                 A*290201 
                 B*3515 
               
               
                 A*290202 
                 B*3516 
               
               
                 A*290203 
                 B*3517 
               
               
                 A*2903 
                 B*3518 
               
               
                 A*2904 
                 B*3519 
               
               
                 A*2905 
                 B*3520 
               
               
                 A*2906 
                 B*3521 
               
               
                 A*2907 
                 B*3522 
               
               
                 A*2908N 
                 B*3523 
               
               
                 A*2909 
                 B*3524 
               
               
                 A*2910 
                 B*3525 
               
               
                 A*2911 
                 B*3526 
               
               
                 A*2912 
                 B*3527 
               
               
                 A*2913 
                 B*3528 
               
               
                 A*2914 
                 B*3529 
               
               
                 A*300101 
                 B*3530 
               
               
                 A*300102 
                 B*3531 
               
               
                 A*300201 
                 B*3532 
               
               
                 A*300202 
                 B*3533 
               
               
                 A*300203 
                 B*3534 
               
               
                 A*3003 
                 B*3535 
               
               
                 A*3004 
                 B*3536 
               
               
                 A*3006 
                 B*3537 
               
               
                 A*3007 
                 B*3538 
               
               
                 A*3008 
                 B*3539 
               
               
                 A*3009 
                 B*3540N 
               
               
                 A*3010 
                 B*3541 
               
               
                 A*3011 
                 B*3542 
               
               
                 A*3012 
                 B*3543 
               
               
                 A*3013 
                 B*3544 
               
               
                 A*3014L 
                 B*3545 
               
               
                 A*3015 
                 B*3546 
               
               
                 A*310102 
                 B*3547 
               
               
                 A*3102 
                 B*3548 
               
               
                 A*3103 
                 B*3549 
               
               
                 A*3104 
                 B*3550 
               
               
                 A*3105 
                 B*3551 
               
               
                 A*3106 
                 B*3552 
               
               
                 A*3107 
                 B*3553N 
               
               
                 A*3108 
                 B*3554 
               
               
                 A*3109 
                 B*3555 
               
               
                 A*3110 
                 B*3556 
               
               
                 A*3111 
                 B*3557 
               
               
                 A*3112 
                 B*3558 
               
               
                 A*3201 
                 B*3559 
               
               
                 A*3202 
                 B*3560 
               
               
                 A*3203 
                 B*3561 
               
               
                 A*3204 
                 B*3701 
               
               
                 A*3205 
                 B*3702 
               
               
                 A*3206 
                 B*3703N 
               
               
                 A*3207 
                 B*3704 
               
               
                 A*3208 
                 B*3705 
               
               
                 A*3209 
                 B*3706 
               
               
                 A*3210 
                 B*3707 
               
               
                 A*3301 
                 B*3708 
               
               
                 A*330301 
                 B*3709 
               
               
                 A*330302 
                 B*3801 
               
               
                 A*3304 
                 B*380201 
               
               
                 A*3305 
                 B*380202 
               
               
                 A*3306 
                 B*3803 
               
               
                 A*3307 
                 B*3804 
               
               
                 A*3308 
                 B*3805 
               
               
                 A*3401 
                 B*3806 
               
               
                 A*3402 
                 B*3807 
               
               
                 A*3403 
                 B*3808 
               
               
                 A*3404 
                 B*3809 
               
               
                 A*3405 
                 B*3810 
               
               
                 A*3406 
                 B*3811 
               
               
                 A*3601 
                 B*39010101 
               
               
                 A*3602 
                 B*39010102L 
               
               
                 A*3603 
                 B*390103 
               
               
                 A*3604 
                 B*390104 
               
               
                 A*4301 
                 B*390201 
               
               
                 A*6601 
                 B*390202 
               
               
                 A*6602 
                 B*3903 
               
               
                 A*6603 
                 B*3904 
               
               
                 A*6604 
                 B*3905 
               
               
                 A*680101 
                 B*390601 
               
               
                 A*680102 
                 B*390602 
               
               
                 A*680103 
                 B*3907 
               
               
                 A*6802 
                 B*3908 
               
               
                 A*680301 
                 B*3909 
               
               
                 A*680302 
                 B*3910 
               
               
                 A*6804 
                 B*3911 
               
               
                 A*6805 
                 B*3912 
               
               
                 A*6806 
                 B*391301 
               
               
                 A*6807 
                 B*391302 
               
               
                 A*6808 
                 B*3914 
               
               
                 A*6809 
                 B*3915 
               
               
                 A*6810 
                 B*3916 
               
               
                 A*6811N 
                 B*3917 
               
               
                 A*6812 
                 B*3918 
               
               
                 A*6813 
                 B*3919 
               
               
                 A*6814 
                 B*3920 
               
               
                 A*6815 
                 B*3922 
               
               
                 A*6816 
                 B*3923 
               
               
                 A*6817 
                 B*3924 
               
               
                 A*6818N 
                 B*3925N 
               
               
                 A*6819 
                 B*3926 
               
               
                 A*6820 
                 B*3927 
               
               
                 A*6821 
                 B*3928 
               
               
                 A*6822 
                 B*3929 
               
               
                 A*6823 
                 B*3930 
               
               
                 A*6824 
                 B*3931 
               
               
                 A*6825 
                 B*3932 
               
               
                 A*6826 
                 B*3933 
               
               
                 A*6827 
                 B*3934 
               
               
                 A*6828 
                 B*400101 
               
               
                 A*6901 
                 B*400102 
               
               
                 A*7401 
                 B*400103 
               
               
                 A*7402 
                 B*400104 
               
               
                 A*7403 
                 B*400105 
               
               
                 A*7404 
                 B*400201 
               
               
                 A*7405 
                 B*400202 
               
               
                 A*7406 
                 B*400203 
               
               
                 A*7407 
                 B*4003 
               
               
                 A*7408 
                 B*4004 
               
               
                 A*7409 
                 B*4005 
               
               
                 A*7410 
                 B*40060101 
               
               
                 A*7411 
                 B*40060102 
               
               
                 A*8001 
                 B*400602 
               
               
                   
                 B*4007 
               
               
                   
                 B*4008 
               
               
                   
                 B*4009 
               
               
                   
                 B*4010 
               
               
                   
                 B*4011 
               
               
                   
                 B*4012 
               
               
                   
                 B*4013 
               
               
                   
                 B*401401 
               
               
                   
                 B*401402 
               
               
                   
                 B*401403 
               
               
                   
                 B*4015 
               
               
                   
                 B*4016 
               
               
                   
                 B*4018 
               
               
                   
                 B*4019 
               
               
                   
                 B*4020 
               
               
                   
                 B*4021 
               
               
                   
                 B*4022N 
               
               
                   
                 B*4023 
               
               
                   
                 B*4024 
               
               
                   
                 B*4025 
               
               
                   
                 B*4026 
               
               
                   
                 B*4027 
               
               
                   
                 B*4028 
               
               
                   
                 B*4029 
               
               
                   
                 B*4030 
               
               
                   
                 B*4031 
               
               
                   
                 B*4032 
               
               
                   
                 B*4033 
               
               
                   
                 B*4034 
               
               
                   
                 B*4035 
               
               
                   
                 B*4036 
               
               
                   
                 B*4037 
               
               
                   
                 B*4038 
               
               
                   
                 B*4039 
               
               
                   
                 B*4040 
               
               
                   
                 B*4042 
               
               
                   
                 B*4043 
               
               
                   
                 B*4044 
               
               
                   
                 B*4045 
               
               
                   
                 B*4046 
               
               
                   
                 B*4047 
               
               
                   
                 B*4048 
               
               
                   
                 B*4049 
               
               
                   
                 B*4050 
               
               
                   
                 B*4051 
               
               
                   
                 B*4052 
               
               
                   
                 B*4053 
               
               
                   
                 B*4054 
               
               
                   
                 B*4055 
               
               
                   
                 B*4056 
               
               
                   
                 B*4057 
               
               
                   
                 B*4058 
               
               
                   
                 B*4059 
               
               
                   
                 B*4060 
               
               
                   
                 B*4061 
               
               
                   
                 B*4101 
               
               
                   
                 B*4102 
               
               
                   
                 B*4103 
               
               
                   
                 B*4104 
               
               
                   
                 B*4105 
               
               
                   
                 B*4106 
               
               
                   
                 B*4107 
               
               
                   
                 B*4201 
               
               
                   
                 B*4202 
               
               
                   
                 B*4204 
               
               
                   
                 B*420501 
               
               
                   
                 B*420502 
               
               
                   
                 B*4206 
               
               
                   
                 B*44020101 
               
               
                   
                 B*44020102S 
               
               
                   
                 B*440202 
               
               
                   
                 B*440203 
               
               
                   
                 B*440301 
               
               
                   
                 B*440302 
               
               
                   
                 B*4404 
               
               
                   
                 B*4405 
               
               
                   
                 B*4406 
               
               
                   
                 B*4407 
               
               
                   
                 B*4408 
               
               
                   
                 B*4409 
               
               
                   
                 B*4410 
               
               
                   
                 B*4411 
               
               
                   
                 B*4412 
               
               
                   
                 B*4413 
               
               
                   
                 B*4414 
               
               
                   
                 B*4415 
               
               
                   
                 B*4416 
               
               
                   
                 B*4417 
               
               
                   
                 B*4418 
               
               
                   
                 B*4419N 
               
               
                   
                 B*4420 
               
               
                   
                 B*4421 
               
               
                   
                 B*4422 
               
               
                   
                 B*4423N 
               
               
                   
                 B*4424 
               
               
                   
                 B*4425 
               
               
                   
                 B*4426 
               
               
                   
                 B*4427 
               
               
                   
                 B*4428 
               
               
                   
                 B*4429 
               
               
                   
                 B*4430 
               
               
                   
                 B*4431 
               
               
                   
                 B*4432 
               
               
                   
                 B*4433 
               
               
                   
                 B*4434 
               
               
                   
                 B*4435 
               
               
                   
                 B*4436 
               
               
                   
                 B*4437 
               
               
                   
                 B*4438 
               
               
                   
                 B*4439 
               
               
                   
                 B*4440 
               
               
                   
                 B*4441 
               
               
                   
                 B*4442 
               
               
                   
                 B*4501 
               
               
                   
                 B*4502 
               
               
                   
                 B*4503 
               
               
                   
                 B*4504 
               
               
                   
                 B*4505 
               
               
                   
                 B*4506 
               
               
                   
                 B*4507 
               
               
                   
                 B*4601 
               
               
                   
                 B*4602 
               
               
                   
                 B*4603 
               
               
                   
                 B*4604 
               
               
                   
                 B*4605 
               
               
                   
                 B*47010101 
               
               
                   
                 B*47010102 
               
               
                   
                 B*4702 
               
               
                   
                 B*4703 
               
               
                   
                 B*4704 
               
               
                   
                 B*4705 
               
               
                   
                 B*4801 
               
               
                   
                 B*4802 
               
               
                   
                 B*4803 
               
               
                   
                 B*4804 
               
               
                   
                 B*4805 
               
               
                   
                 B*4806 
               
               
                   
                 B*4807 
               
               
                   
                 B*4808 
               
               
                   
                 B*4809 
               
               
                   
                 B*4810 
               
               
                   
                 B*4811 
               
               
                   
                 B*4812 
               
               
                   
                 B*4813 
               
               
                   
                 B*4901 
               
               
                   
                 B*4902 
               
               
                   
                 B*4903 
               
               
                   
                 B*4904 
               
               
                   
                 B*5001 
               
               
                   
                 B*5002 
               
               
                   
                 B*5004 
               
               
                   
                 B*510101 
               
               
                   
                 B*510102 
               
               
                   
                 B*510103 
               
               
                   
                 B*510104 
               
               
                   
                 B*510105 
               
               
                   
                 B*510106 
               
               
                   
                 B*510107 
               
               
                   
                 B*510201 
               
               
                   
                 B*510202 
               
               
                   
                 B*5103 
               
               
                   
                 B*5104 
               
               
                   
                 B*5105 
               
               
                   
                 B*5106 
               
               
                   
                 B*5107 
               
               
                   
                 B*5108 
               
               
                   
                 B*5109 
               
               
                   
                 B*5110 
               
               
                   
                 B*5111N 
               
               
                   
                 B*5112 
               
               
                   
                 B*511301 
               
               
                   
                 B*511302 
               
               
                   
                 B*5114 
               
               
                   
                 B*5115 
               
               
                   
                 B*5116 
               
               
                   
                 B*5117 
               
               
                   
                 B*5118 
               
               
                   
                 B*5119 
               
               
                   
                 B*5120 
               
               
                   
                 B*5121 
               
               
                   
                 B*5122 
               
               
                   
                 B*5123 
               
               
                   
                 B*5124 
               
               
                   
                 B*5126 
               
               
                   
                 B*5127N 
               
               
                   
                 B*5128 
               
               
                   
                 B*5129 
               
               
                   
                 B*5130 
               
               
                   
                 B*5131 
               
               
                   
                 B*5132 
               
               
                   
                 B*5133 
               
               
                   
                 B*5134 
               
               
                   
                 B*5135 
               
               
                   
                 B*5136 
               
               
                   
                 B*5137 
               
               
                   
                 B*5138 
               
               
                   
                 B*520101 
               
               
                   
                 B*520102 
               
               
                   
                 B*520103 
               
               
                   
                 B*520104 
               
               
                   
                 B*5202 
               
               
                   
                 B*5203 
               
               
                   
                 B*5204 
               
               
                   
                 B*5205 
               
               
                   
                 B*5206 
               
               
                   
                 B*5207 
               
               
                   
                 B*5208 
               
               
                   
                 B*530101 
               
               
                   
                 B*530102 
               
               
                   
                 B*530103 
               
               
                   
                 B*5302 
               
               
                   
                 B*5303 
               
               
                   
                 B*5304 
               
               
                   
                 B*5305 
               
               
                   
                 B*5306 
               
               
                   
                 B*5307 
               
               
                   
                 B*5308 
               
               
                   
                 B*5309 
               
               
                   
                 B*5310 
               
               
                   
                 B*5401 
               
               
                   
                 B*5402 
               
               
                   
                 B*5403 
               
               
                   
                 B*5404 
               
               
                   
                 B*5405N 
               
               
                   
                 B*5406 
               
               
                   
                 B*5407 
               
               
                   
                 B*550101 
               
               
                   
                 B*550102 
               
               
                   
                 B*5502 
               
               
                   
                 B*5503 
               
               
                   
                 B*5504 
               
               
                   
                 B*5505 
               
               
                   
                 B*5507 
               
               
                   
                 B*5508 
               
               
                   
                 B*5509 
               
               
                   
                 B*5510 
               
               
                   
                 B*5511 
               
               
                   
                 B*5512 
               
               
                   
                 B*5513 
               
               
                   
                 B*5514 
               
               
                   
                 B*5515 
               
               
                   
                 B*5516 
               
               
                   
                 B*5517 
               
               
                   
                 B*5518 
               
               
                   
                 B*5519 
               
               
                   
                 B*5601 
               
               
                   
                 B*5602 
               
               
                   
                 B*5603 
               
               
                   
                 B*5604 
               
               
                   
                 B*560501 
               
               
                   
                 B*560502 
               
               
                   
                 B*5606 
               
               
                   
                 B*5607 
               
               
                   
                 B*5608 
               
               
                   
                 B*5609 
               
               
                   
                 B*5610 
               
               
                   
                 B*5611 
               
               
                   
                 B*5612 
               
               
                   
                 B*5613 
               
               
                   
                 B*5614 
               
               
                   
                 B*5615 
               
               
                   
                 B*5616 
               
               
                   
                 B*570101 
               
               
                   
                 B*570102 
               
               
                   
                 B*570103 
               
               
                   
                 B*5702 
               
               
                   
                 B*570301 
               
               
                   
                 B*570302 
               
               
                   
                 B*5704 
               
               
                   
                 B*5705 
               
               
                   
                 B*5706 
               
               
                   
                 B*5707 
               
               
                   
                 B*5708 
               
               
                   
                 B*5709 
               
               
                   
                 B*5801 
               
               
                   
                 B*5802 
               
               
                   
                 B*5804 
               
               
                   
                 B*5805 
               
               
                   
                 B*5806 
               
               
                   
                 B*5807 
               
               
                   
                 B*5808 
               
               
                   
                 B*5809 
               
               
                   
                 B*5810N 
               
               
                   
                 B*5811 
               
               
                   
                 B*5901 
               
               
                   
                 B*670101 
               
               
                   
                 B*670102 
               
               
                   
                 B*6702 
               
               
                   
                 B*7301 
               
               
                   
                 B*7801 
               
               
                   
                 B*780201 
               
               
                   
                 B*780202 
               
               
                   
                 B*7803 
               
               
                   
                 B*7804 
               
               
                   
                 B*7805 
               
               
                   
                 B*8101 
               
               
                   
                 B*8102 
               
               
                   
                 B*8201 
               
               
                   
                 B*8202 
               
               
                   
                 B*8301 
               
               
                   
                 B*9501 
               
               
                   
                 B*9502 
               
               
                   
                 B*9503 
               
               
                   
                 B*9504 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Monoclonal antibodies used to treat cancer, their target and 
               
               
                 mechanism of action. 
               
            
           
           
               
               
            
               
                 Name of monoclonal antibody 
                 Target/Mechanism of action 
               
               
                   
               
               
                 Rituximab (Rituxan ®) 
                 Used to treat B-cell lymphomas, acts 
               
               
                   
                 by binding to the CD20 molecule 
               
               
                   
                 present on all B cells. 
               
               
                 Herceptin ® 
                 Binds to HER2, a growth factor 
               
               
                   
                 receptor found on some tumour cells, 
               
               
                   
                 such as breast cancers and 
               
               
                   
                 lymphomas. 
               
               
                 Alemtuzumab (MabCampath ®) 
                 Used to treat chronic lymphocytic 
               
               
                   
                 leukaemia. Binds to the CD52 
               
               
                   
                 molecule found on all white blood 
               
               
                   
                 cells. 
               
               
                 Lym-1 (Oncolym ®) 
                 Used to treat lymphoma. Binds to the 
               
               
                   
                 histocompatibility antigen found on 
               
               
                   
                 lymphoma cells. 
               
               
                 Bevacizumab (Avastin ®) 
                 Used to treat tumours. Binds to 
               
               
                   
                 vascular endothelial growth factor, 
               
               
                   
                 which is found in healthy as well as 
               
               
                   
                 malignant cells. 
               
               
                 Cetuximab (Erbitux ®) 
                 Used to treat colorectal cancers. 
               
               
                   
                 Binds to epidermal growth factor 
               
               
                   
                 receptor, which is also found on 
               
               
                   
                 normal epithelial cells. 
               
               
                 Telomerase antibody 
                 Used to treat cancers in general. 
               
               
                   
                 Binds to telomerase, which is the 
               
               
                   
                 protein responsible for cancer cells 
               
               
                   
                 over-riding the usual apoptosis 
               
               
                   
                 mechanisms. This protein is also 
               
               
                   
                 present on normal cells. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Host cell proteins known to be targeted for degradation 
               
               
                 following binding to HPV E6 or E7 proteins. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Host cell 
                 HPV 
                   
                 Gene 
                 Accession 
                   
                   
                   
               
               
                 target* 
                 protein 
                 Other names 
                 name 
                 number 
                 Function 
                 Location 
                 Reference 
               
               
                   
               
               
                 Retinoblastoma 1 
                 E7 
                 Retinoblastoma 
                 RB1 
                 M15400 
                 cell cycle 
                 Nuclear 
                 (19) 
               
               
                   
                   
                 susceptibility 
                   
                   
                 regulation, 
               
               
                   
                   
                 protein 
                   
                   
                 tumour 
               
               
                   
                   
                   
                   
                   
                 suppressor 
               
               
                 E6AP 
                 E6 
                 Human 
                 UBE3A 
                 AF002224 
                 proteolysis; 
                 Cytosolic 
                 (24) 
               
               
                   
                   
                 papillomavirus E6 
                   
                   
                 binds to 
               
               
                   
                   
                 associated 
                   
                   
                 HPV16&amp;18 
               
               
                   
                   
                 protein 
                   
                   
                 E6 to target 
               
               
                   
                   
                 (E6AP), Ubiquitin 
                   
                   
                 p53 for 
               
               
                   
                   
                 protein ligase 
                   
                   
                 degradation, 
               
               
                   
                   
                 E3A (UBE3A) 
                   
                   
                 can also 
               
               
                   
                   
                   
                   
                   
                 target itself 
               
               
                   
                   
                   
                   
                   
                 for 
               
               
                   
                   
                   
                   
                   
                 ubiquination 
               
               
                   
                   
                   
                   
                   
                 and 
               
               
                   
                   
                   
                   
                   
                 degradation 
               
               
                 C-MYC 
                 E6 
                 v-myc 
                 MYC 
                 AY214166 
                 cell cycle, 
                 Nuclear 
                 (25) 
               
               
                   
                   
                 myelocytomatosis 
                   
                   
                 gene 
               
               
                   
                   
                 viral oncogene 
                   
                   
                 transcription 
               
               
                   
                   
                 homolog (avian), 
               
               
                   
                   
                 myc proto- 
               
               
                   
                   
                 oncogene 
               
               
                   
                   
                 product 
               
               
                 HSCRIB 
                 E6 
                 scribbled 
                 SCRIB 
                 AY062238 
                 cell cycle 
                 membrane 
                 (26) 
               
               
                   
                   
                 homologue, vartul 
               
               
                 HMCM7 
                 E6 
                 minichromosome 
                 MCM7 
                 AB004270 
                 DNA 
                 nuclear 
                 (27) 
               
               
                   
                   
                 maintenance 
                   
                   
                 replication 
               
               
                   
                   
                 deficient 
               
               
                   
                   
                 7, CDC47 
               
               
                 MAGI1 
                 E6 
                 membrane 
                 MAGI1 
                 AB010894 
                 Signalling, 
                 membrane 
                 (28) 
               
               
                   
                   
                 associated 
                   
                   
                 tight 
               
               
                   
                   
                 guanylate kinase, 
                   
                   
                 junctions, 
               
               
                   
                   
                 WW and PDZ 
                   
                   
                 cell 
               
               
                   
                   
                 domain 
                   
                   
                 adhesion 
               
               
                   
                   
                 containing 
               
               
                   
                   
                 1, BAIAP1, BAP1, 
               
               
                   
                   
                 MAGI-1, AIP3 
               
               
                 SIPA1L1 
                 E6 
                 signal-induced 
                 SIPA1L1 
                 AB007900 
                 GTPase 
                 membrane 
                 (29) 
               
               
                   
                   
                 proliferation- 
                   
                   
                 activating 
               
               
                   
                   
                 associated 1 like 
                   
                   
                 protein 
               
               
                   
                   
                 1, E6 targetted 
               
               
                   
                   
                 protein 1 (E6TP1) 
               
               
                 DLG1 
                 E6 
                 discs, large 
                 DLG1 
                 U13897 
                 cell growth, 
                 membrane 
                 (30) 
               
               
                   
                   
                 homolog 1 
                   
                   
                 adhesion, 
               
               
                   
                   
                 (DLG1, HDLG), 
                   
                   
                 signalling 
               
               
                   
                   
                 synapse 
               
               
                   
                   
                 associated 
               
               
                   
                   
                 protein 97 
               
               
                   
                   
                 (SAP97), hdlg 
               
               
                 BAK 
                 E6 
                 BCL2- 
                 BAK1 
                 U23765 
                 pro- 
                 membrane 
                 (31) 
               
               
                   
                   
                 antagonist/killer 1 
                   
                   
                 apoptotic, in 
               
               
                   
                   
                   
                   
                   
                 presence of 
               
               
                   
                   
                   
                   
                   
                 appropriate 
               
               
                   
                   
                   
                   
                   
                 stimuli binds 
               
               
                   
                   
                   
                   
                   
                 to BCL-2 to 
               
               
                   
                   
                   
                   
                   
                 accelerate 
               
               
                   
                   
                   
                   
                   
                 cell death 
               
               
                 MPDZ 
                 E6 
                 multiple PDZ 
                 MPDZ 
                 AF093419 
                 tight 
                 membrane 
                 (32) 
               
               
                   
                   
                 domain protein 
                   
                   
                 junction 
               
               
                   
                   
                 (MUPP1) 
                   
                   
                 formation 
               
               
                 MGMT 
                 E6 
                 O-6- 
                 MGMT 
                 M29971 
                 DNA repair 
                 nuclear 
                 (33) 
               
               
                   
                   
                 methylguanine- 
               
               
                   
                   
                 DNA 
               
               
                   
                   
                 methyltransferase 
               
               
                 MAGI-2 
                 E6 
                 membrane 
                 MAGI2 
                 AB014605 
                 same as 
                 membrane 
                 (34) 
               
               
                   
                   
                 associated 
                   
                   
                 magi-1 
               
               
                   
                   
                 guanylate kinase, 
               
               
                   
                   
                 WW and PDZ 
               
               
                   
                   
                 domain 
               
               
                   
                   
                 containing 2, 
               
               
                   
                   
                 activin receptor 
               
               
                   
                   
                 interacting protein 
               
               
                   
                   
                 1 (ARIP1) 
               
               
                 MAGI-3 
                 E6 
                 membrane 
                 MAGI3 
                 AF213259 
                 same as 
                 membrane 
                 (34) 
               
               
                   
                   
                 associated 
                   
                   
                 magi-1 
               
               
                   
                   
                 guanylate kinase, 
               
               
                   
                   
                 WW and PDZ 
               
               
                   
                   
                 domain 
               
               
                   
                   
                 containing 3 
               
               
                 Tuberin 
                 E6 
                 tuberous 
                 TSC2 
                 AB014460 
                 tumour 
                 membrane 
                 (35) 
               
               
                   
                   
                 sclerosis 2 
                   
                   
                 suppressor, 
               
               
                   
                   
                 (TSC2) 
                   
                   
                 GTPase 
               
               
                   
                   
                   
                   
                   
                 signalling 
               
               
                 N-MYC 
                 E6 
                 v-myc 
                 MYCN 
                 M13228 
                 tumour 
                 membrane 
                 (25) 
               
               
                   
                   
                 myelocytomatosis 
                   
                   
                 suppressor 
               
               
                   
                   
                 viral related 
               
               
                   
                   
                 oncogene, neuro- 
               
               
                   
                   
                 blastoma derived 
               
               
                   
                   
                 (avian), N-MYC 
               
               
                   
                   
                 proto-oncogene 
               
               
                   
                   
                 protein 
               
               
                   
               
               
                 *Proteins are listed by their agreed standard names, rather than the published names. 
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Host cell proteins and HLA-A*0201 binding 
                   
               
               
                 peptides 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Starting 
                   
                   
                 SEQ ID 
                   
               
               
                 Protein 
                 Pos 
                 Sequence 
                 T0.5 
                 NO. 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Retinoblastoma 
                 563 
                 WLSDsPLFDL 
                 5375 
                 1 
                   
               
               
                   
               
               
                 Retinoblastoma 
                 475 
                 KLLNdNIFHM 
                 858 
                 2 
               
               
                   
               
               
                 Retinoblastoma 
                 75 
                 WLTWeKVSSV 
                 736 
                 3 
               
               
                   
               
               
                 Retinoblastoma 
                 646 
                 SLSLFYKKV 
                 396 
                 4 
               
               
                   
               
               
                 Retinoblastoma 
                 447 
                 KLGVrLYYRV 
                 365 
                 5 
               
               
                   
               
               
                 Retinoblastoma 
                 218 
                 LMLCvLDYFI 
                 261 
                 6 
               
               
                   
               
               
                 Retinoblastoma 
                 485 
                 SLLACALEV 
                 257 
                 7 
               
               
                   
               
               
                 Retinoblastoma 
                 157 
                 VLFALFSKL 
                 255 
                 8 
               
               
                   
               
               
                 Retinoblastoma 
                 648 
                 SLFYkKVYRL 
                 182 
                 9 
               
               
                   
               
               
                 Retinoblastoma 
                 824 
                 KMTPrSRILV 
                 176 
                 10 
               
               
                   
               
               
                 Retinoblastoma 
                 679 
                 IIWTIFQHTL 
                 157 
                 11 
               
               
                   
               
               
                 Retinoblastoma 
                 188 
                 ALVLKVSWI 
                 132 
                 12 
               
               
                   
               
               
                 Retinoblastoma 
                 76 
                 LTWEKVSSV 
                 129 
                 13 
               
               
                   
               
               
                 Retinoblastoma 
                 703 
                 IMMCSMYGI 
                 109 
                 14 
               
               
                   
               
               
                 Retinoblastoma 
                 900 
                 KLAEmTSTRT 
                 107 
                 15 
               
               
                   
               
               
                 Retinoblastoma 
                 219 
                 MLCVLDYFI 
                 98 
                 16 
               
               
                   
               
               
                 BAK 
                 150 
                 FLGQvTRFVV 
                 761 
                 17 
               
               
                   
               
               
                 BAK 
                 129 
                 ALLGFGYRL 
                 300 
                 18 
               
               
                   
               
               
                 BAK 
                 188 
                 ILNVIVVLGV 
                 272 
                 19 
               
               
                   
               
               
                 BAK 
                 182 
                 NLGNgPILNV 
                 160 
                 20 
               
               
                   
               
               
                 BAK 
                 195 
                 VVLLGQFVV 
                 91 
                 21 
               
               
                   
               
               
                 BAK 
                 191 
                 VLVVIGVVLL 
                 84 
                 22 
               
               
                   
               
               
                 BAK 
                 145 
                 GLTGFLGQV 
                 79 
                 23 
               
               
                   
               
               
                 DLG 
                 355 
                 ALYDRLADV 
                 2099 
                 24 
               
               
                   
               
               
                 DLG 
                 275 
                 NLHGvFVAEV 
                 608 
                 25 
               
               
                   
               
               
                 DLG 
                 345 
                 GLPGDSFYI 
                 333 
                 26 
               
               
                   
               
               
                 DLG 
                 148 
                 QLLEfNGINL 
                 324 
                 27 
               
               
                   
               
               
                 DLG 
                 666 
                 VLWIPACPL 
                 301 
                 28 
               
               
                   
               
               
                 DLG 
                 497 
                 VLILgPLLDV 
                 272 
                 29 
               
               
                   
               
               
                 DLG 
                 301 
                 LILEyGSLDV 
                 247 
                 30 
               
               
                   
               
               
                 DLG 
                 480 
                 SLAYqRVQKV 
                 160 
                 31 
               
               
                   
               
               
                 DLG 
                 498 
                 LILGPLLDV 
                 138 
                 32 
               
               
                   
               
               
                 DLG 
                 178 
                 ILAQYNPHV 
                 118 
                 33 
               
               
                   
               
               
                 E6AP 
                 127 
                 YLTEeKVYEI 
                 453 
                 34 
               
               
                   
               
               
                 E6AP 
                 449 
                 FINEPLNEV 
                 415 
                 35 
               
               
                   
               
               
                 E6AP 
                 748 
                 YLFRpEEIEL 
                 364 
                 36 
               
               
                   
               
               
                 E6AP 
                 657 
                 VLYQSLKDL 
                 267 
                 37 
               
               
                   
               
               
                 E6AP 
                 785 
                 VLIREFWEI 
                 253 
                 38 
               
               
                   
               
               
                 E6AP 
                 226 
                 KLGPDDVSV 
                 243 
                 39 
               
               
                   
               
               
                 E6AP 
                 283 
                 YLNLFIIGM 
                 200 
                 40 
               
               
                   
               
               
                 E6AP 
                 785 
                 VLIReFWEIV 
                 153 
                 41 
               
               
                   
               
               
                 E6AP 
                 477 
                 FMTCpFILNA 
                 144 
                 42 
               
               
                   
               
               
                 E6AP 
                 262 
                 YLSPnVECDL 
                 98 
                 43 
               
               
                   
               
               
                 C-MYC 
                 133 
                 CMWSgFSAAA 
                 113 
                 44 
               
               
                   
               
               
                 C-MYC 
                 68 
                 GLCSpCYVAV 
                 104 
                 45 
               
               
                   
               
               
                 C-MYC 
                 177 
                 YLQDLSAAA 
                 94 
                 46 
               
               
                   
               
               
                 C-MYC 
                 133 
                 CMWSGFSAA 
                 57 
                 47 
               
               
                   
               
               
                 MUPP1 
                 745 
                 LLPGdRLMFV 
                 1496 
                 48 
               
               
                   
               
               
                 MUPP1 
                 692 
                 AMWEaGIQHI 
                 590 
                 49 
               
               
                   
               
               
                 MUPP1 
                 607 
                 LLGENHQDV 
                 485 
                 50 
               
               
                   
               
               
                 MUPP1 
                 981 
                 YLLEQSSLA 
                 347 
                 51 
               
               
                   
               
               
                 MUPP1 
                 1650 
                 LLGAiIIHEV 
                 272 
                 52 
               
               
                   
               
               
                 MUPP1 
                 814 
                 GLADkPLFRA 
                 272 
                 53 
               
               
                   
               
               
                 MUPP1 
                 606 
                 TLLGeNHQDV 
                 257 
                 54 
               
               
                   
               
               
                 MUPP1 
                 1547 
                 SLLKtAKMTV 
                 257 
                 55 
               
               
                   
               
               
                 MUPP1 
                 1772 
                 ILMVNGEDV 
                 214 
                 56 
               
               
                   
               
               
                 MUPP1 
                 1524 
                 KVGDQILAV 
                 201 
                 57 
               
               
                   
               
               
                 MUPP1 
                 1766 
                 LMQGdQILMV 
                 196 
                 58 
               
               
                   
               
               
                 MUPP1 
                 592 
                 KLFSGDELL 
                 136 
                 59 
               
               
                   
               
               
                 MUPP1 
                 87 
                 TLQNESFLL 
                 124 
                 60 
               
               
                   
               
               
                 MUPP1 
                 312 
                 GMSSeQVAQV 
                 116 
                 61 
               
               
                   
               
               
                 MUPP1 
                 751 
                 LMFVNDVNL 
                 97 
                 62 
               
               
                   
               
               
                 E6TP1 
                 855 
                 SMGAIVWAV 
                 867 
                 63 
               
               
                   
               
               
                 E6TP1 
                 886 
                 VLIEgETKSV 
                 485 
                 64 
               
               
                   
               
               
                 E6TP1 
                 960 
                 GLGQLCFHV 
                 403 
                 65 
               
               
                   
               
               
                 E6TP1 
                 877 
                 LLGIsNEFIV 
                 281 
                 66 
               
               
                   
               
               
                 E6TP1 
                 1009 
                 QMIDILRTSV 
                 206 
                 67 
               
               
                   
               
               
                 E6TP1 
                 1592 
                 VLFSsTYPSL 
                 202 
                 68 
               
               
                   
               
               
                 E6TP1 
                 783 
                 FLLAKVINA 
                 194 
                 69 
               
               
                   
               
               
                 E6TP1 
                 45 
                 SLGSsVMAPV 
                 160 
                 70 
               
               
                   
               
               
                 E6TP1 
                 641 
                 FLQLLGERV 
                 157 
                 71 
               
               
                   
               
               
                 E6TP1 
                 339 
                 ILFDLNEAI 
                 132 
                 72 
               
               
                   
               
               
                 E6TP1 
                 1522 
                 KLIDLESPT 
                 107 
                 73 
               
               
                   
               
               
                 MAGI-1 
                 69 
                 LLLEvQCVRV 
                 1794 
                 74 
               
               
                   
               
               
                 MAGI-1 
                 262 
                 TLQEtALPPV 
                 656 
                 75 
               
               
                   
               
               
                 MAGI-1 
                 1054 
                 KVGDRILAV 
                 201 
                 76 
               
               
                   
               
               
                 MAGI-1 
                 161 
                 FLTVkEFLDL 
                 187 
                 77 
               
               
                   
               
               
                 MAGI-1 
                 80 
                 GLPRyDVLGV 
                 160 
                 78 
               
               
                   
               
               
                 MAGI-1 
                 717 
                 LLVQrGCLPV 
                 118 
                 79 
               
               
                   
               
               
                 MAGI-1 
                 527 
                 VLGHTHAQV 
                 118 
                 80 
               
               
                   
               
               
                 MCM7 
                 356 
                 RLAQHITYV 
                 880 
                 81 
               
               
                   
               
               
                 MCM7 
                 335 
                 LLSRfDLLWL 
                 459 
                 82 
               
               
                   
               
               
                 MCM7 
                 60 
                 KMQEHSDQV 
                 353 
                 83 
               
               
                   
               
               
                 MCM7 
                 259 
                 VLADgGVCCI 
                 167 
                 84 
               
               
                   
               
               
                 MCM7 
                 439 
                 ALARIRMVDV 
                 160 
                 85 
               
               
                   
               
               
                 MCM7 
                 381 
                 KLMRrYIAMC 
                 148 
                 86 
               
               
                   
               
               
                 MCM7 
                 178 
                 LLLLLVGGV 
                 131 
                 87 
               
               
                   
               
               
                 MCM7 
                 481 
                 ALDEyEELNV 
                 114 
                 88 
               
               
                   
               
               
                 MCM7 
                 273 
                 KMAEaDRTAI 
                 108 
                 89 
               
               
                   
               
               
                 Vartul 
                 713 
                 KLLEvNGVAL 
                 1134 
                 90 
               
               
                   
               
               
                 Vartul 
                 99 
                 SLPAsLSFLV 
                 403 
                 91 
               
               
                   
               
               
                 Vartul 
                 348 
                 YLLPQQPPL 
                 364 
                 92 
               
               
                   
               
               
                 Vartul 
                 229 
                 ILTEnLLMAL 
                 342 
                 93 
               
               
                   
               
               
                 Vartul 
                 244 
                 KLTKITNLNV 
                 243 
                 94 
               
               
                   
               
               
                 Vartul 
                 15 
                 FMQLVELDV 
                 231 
                 95 
               
               
                   
               
               
                 Vartul 
                 1199 
                 KLDYrALAAV 
                 224 
                 96 
               
               
                   
               
               
                 Vartul 
                 68 
                 ALNDvSLQAL 
                 201 
                 97 
               
               
                   
               
               
                 Vartul 
                 63 
                 SLAHIALNDV 
                 160 
                 98 
               
               
                   
               
               
                 Vartul 
                 992 
                 ILAVNGQDV 
                 118 
                 99 
               
               
                   
               
               
                 Vartul 
                 849 
                 VLSINGVDV 
                 118 
                 100 
               
               
                   
               
               
                 Vartul 
                 129 
                 ALPNIRELWL 
                 117 
                 101 
               
               
                   
               
               
                 MGMT 
                 98 
                 VLWKLLKVV 
                 925 
                 102 
               
               
                   
               
               
                 MGMT 
                 161 
                 GLAVKEWLL 
                 160 
                 103 
               
               
                   
               
               
                 MGMT 
                 167 
                 WLLAhEGHRL 
                 364 
                 104 
               
               
                   
               
               
                 MGMT 
                 89 
                 FQQEsFTRQV 
                 101 
                 105 
               
               
                   
               
               
                 N-Myc 
                 421 
                 VILKkATEYV 
                 162 
                 106 
               
               
                   
               
               
                   
                 440 
                 LLLEkEKLQA 
                 128 
                 107 
               
               
                   
               
               
                   
                 446 
                 KLQArQQQLL 
                 75 
                 108 
               
               
                   
               
               
                 MAGI-2 
                 65 
                 LLLEvNETPV 
                 1794 
                 109 
               
               
                   
               
               
                   
                 993 
                 KLIKdAGLSV 
                 243 
                 110 
               
               
                   
               
               
                   
                 970 
                 KVGDRILAV 
                 201 
                 111 
               
               
                   
               
               
                   
                 43 
                 YLGEvKPGKV 
                 171 
                 112 
               
               
                   
               
               
                   
                 76 
                 GLTIrDVLAV 
                 160 
                 113 
               
               
                   
               
               
                   
                 528 
                 AIMERPPPV 
                 145 
                 114 
               
               
                   
               
               
                   
                 751 
                 AIYESRQQV 
                 125 
                 115 
               
               
                   
               
               
                   
                 481 
                 VLGHTHADV 
                 118 
                 116 
               
               
                   
               
               
                   
                 639 
                 GLCEGDLIV 
                 117 
                 117 
               
               
                   
               
               
                   
                 65 
                 LLLEvNETPV 
                 1794 
                 118 
               
               
                   
               
               
                   
                 993 
                 KLIKdAGLSV 
                 243 
                 119 
               
               
                   
               
               
                   
                 970 
                 KVGDRILAV 
                 201 
                 120 
               
               
                   
               
               
                   
                 43 
                 YLGEvKPGKV 
                 171 
                 121 
               
               
                   
               
               
                   
                 76 
                 GLTIrDVLAV 
                 160 
                 122 
               
               
                   
               
               
                   
                 528 
                 AIMERPPPV 
                 145 
                 123 
               
               
                   
               
               
                   
                 751 
                 AIYESRQQV 
                 125 
                 124 
               
               
                   
               
               
                   
                 481 
                 VLGHTHADV 
                 118 
                 125 
               
               
                   
               
               
                   
                 639 
                 GLCEGDLIV 
                 117 
                 126 
               
               
                   
               
               
                 MAGI-3 
                 70 
                 VLLEvNGTPV 
                 1794 
                 127 
               
               
                   
               
               
                   
                 502 
                 FQLVpVNQYV 
                 660 
                 128 
               
               
                   
               
               
                   
                 503 
                 QLVPVNQYV 
                 383 
                 129 
               
               
                   
               
               
                   
                 11 
                 WLSKvQECAV 
                 320 
                 130 
               
               
                   
               
               
                   
                 923 
                 KVGDHISAV 
                 201 
                 131 
               
               
                   
               
               
                   
                 726 
                 KLDPSEVYL 
                 164 
                 132 
               
               
                   
               
               
                   
                 654 
                 NLTHIQVVEV 
                 160 
                 133 
               
               
                   
               
               
                   
                 200 
                 FQPDPVDQV 
                 150 
                 134 
               
               
                   
               
               
                   
                 1067 
                 NMGLFILRL 
                 135 
                 135 
               
               
                   
               
               
                   
                 1121 
                 LLLLrPGTGL 
                 134 
                 136 
               
               
                   
               
               
                   
                 1122 
                 LLLRPGTGL 
                 134 
                 137 
               
               
                   
               
               
                   
                 499 
                 VQMFQLVPV 
                 102 
                 138 
               
               
                   
               
               
                   
                 70 
                 VLLEvNGTPV 
                 98 
                 139 
               
               
                   
               
               
                   
                 502 
                 FQLVpVNQYV 
                 91 
                 140 
               
               
                   
               
               
                   
                 503 
                 QLVPVNQYV 
                 85 
                 141 
               
               
                   
               
               
                   
                 11 
                 WLSKvQECAV 
                 79 
                 142 
               
               
                   
               
               
                 Tuberin 
                 464 
                 KVLDVLSFV 
                 4088 
                 143 
               
               
                   
               
               
                   
                 176 
                 FLLVLVNLV 
                 2723 
                 144 
               
               
                   
               
               
                   
                 1060 
                 WLVGnKLVTV 
                 736 
                 145 
               
               
                   
               
               
                   
                 291 
                 LLRGAVFFV 
                 659 
                 146 
               
               
                   
               
               
                   
                 1702 
                 IVSDrNLPFV 
                 537 
                 147 
               
               
                   
               
               
                   
                 80 
                 ALWKAVADL 
                 408 
                 148 
               
               
                   
               
               
                   
                 1208 
                 WLMSLENPL 
                 364 
                 149 
               
               
                   
               
               
                   
                 688 
                 LLFRvLLQCL 
                 309 
                 150 
               
               
                   
               
               
                   
                 117 
                 GVLRaLFFKV 
                 248 
                 151 
               
               
                   
               
               
                   
                 1065 
                 KLVTVTTSV 
                 243 
                 152 
               
               
                   
               
               
                   
                 464 
                 KVLDvLSFVL 
                 236 
                 153 
               
               
                   
               
               
                   
                 155 
                 YLEEeLADFV 
                 226 
                 154 
               
               
                   
               
               
                   
                 258 
                 KLMRNLLGT 
                 222 
                 155 
               
               
                   
               
               
                   
                 1033 
                 YVFSNFTAV 
                 197 
                 156 
               
               
                   
               
               
                   
                 235 
                 SLPLFIVTL 
                 187 
                 157 
               
               
                   
               
               
                   
                 612 
                 LQAFdFLFLL 
                 187 
                 158 
               
               
                   
               
               
                   
                 617 
                 FLFLIRADSL 
                 178 
                 159 
               
               
                   
               
               
                   
                 506 
                 KLATgLLVDL 
                 172 
                 160 
               
               
                   
               
               
                   
                 360 
                 ILLNIIERL 
                 151 
                 161 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Summary of peptide binding 
               
            
           
           
               
               
               
            
               
                   
                   
                 No. peptides 
               
               
                   
                 Source protein 
                 binding 
               
               
                   
                   
               
               
                   
                 BAK 
                 6/7 
               
               
                   
                 DLG 
                  7/10 
               
               
                   
                 CMYC 
                 2/4 
               
               
                   
                 E6AP 
                  9/10 
               
               
                   
                 MUPP1 
                 13/15 
               
               
                   
                 Retinoblastoma 
                  6/16 
               
               
                   
                 Total 
                 43/62 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Frequency of CD8 +  T cells recognising Rb peptide in healthy 
               
               
                 volunteers. 
               
               
                 Peripheral blood lymphocytes from HLA-A2 +  healthy donors were 
               
               
                 enriched for CD8 +  T cells, then cultured for 14 days with Rb7 peptide 
               
               
                 and antigen presenting cells (APC) or Melan-A (Mart1 26-35 ) peptide. 
               
               
                 Cells were harvested and tested with HLA-A2/Rb7 pentamer or 
               
               
                 HLA-A2/Melan-A pentamer. 
               
               
                 The numbers of CD8 +  pentamer +  T lymphocytes were measured 
               
               
                 by flow cytometry, excluding dead and CD14 +  cells. 
               
            
           
           
               
               
               
            
               
                   
                 Frequency of 
                   
               
               
                   
                 CD8 +  pentamer +  cells 
               
            
           
           
               
               
               
            
               
                 Donor 
                 Rb 
                 Melan A 
               
               
                   
               
               
                 1 
                 1/2500 
                  1/24 
               
               
                 2 
                 1/1000 
                 1/4 
               
               
                 3 
                 1/1000 
                 1/3 
               
               
                 4 
                 1/909  
                 1/3 
               
               
                 5 
                 1/120  
                 1/4 
               
               
                 6 
                 1/3333 
                  1/208 
               
               
                 7 
                 1/2000 
                 1/3 
               
               
                 8 
                 1/2500 
                 1/3 
               
               
                   
               
            
           
         
       
     
     REFERENCES 
     
         
         1. Mandelboim, O., E. Vadai, M. Fridkin, A. Katz-Hillel, M. Feldman, G. Berke, and L. Eisenbach. 1995. Regression of established murine carcinoma metastases following vaccination with tumour-associated antigen peptides.  Nature Medicine.  1:1179. 
         2. Heslop, H. E., and C. M. Rooney. 1997. Adoptive cellular immunotherapy for EBV lymphoproliferative disease.  Immunological Reviews  157:217. 
         3. Overwijk, W. W., D. S. Lee, D. R. Surman, K. R. Irvine, C. E. Touloukian, C. C. Chan, M. W. Carroll, B. Moss, S. A. Rosenberg, and N. P. Restifo. 1999. Vaccination with a recombinant vaccinia virus encoding a ‘self’ antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes.  Proceedings of the National Academy of Sciences of the United States of America  96:2982. 
         4. Gao, L., I. Bellantuono, A. Elsasser, S. B. Marley, M. Y. Gordon, J. M. Goldman, and H. J. Stauss. 2000. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1.  Blood  95:2198. 
         5. Theobald, M., J. Biggs, D. Dittmer, A. J. Levine, and L. A. Sherman. 1996. Targeting p53 as a general tumour antigen.  Proceedings of the National Academy of Sciences of the United States of America  92:11993. 
         6. Walboomers, J. M., M. V. Jacobs, M. M. Manos, F. X. Bosch, J. A. Kummer, K. V. Shah, P. J. Snijders, J. Peto, C. J. Meijer, and N. Munoz. 1999. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.  Journal of Pathology  189:12. 
         7. Borysiewicz, L. K., A. Fiander, M. Nimako, S. Man, G. W. G. Wilkinson, D. Westmoreland, A. S. Evans, M. Adams, S. N. Stacey, M. E. G. Boursnell, E. Rutherford, J. K. Hickling, and S. C. Inglis. 1996. A recombinant vaccinia virus encoding human papillomavirus type 16 and type 18, e6 and e7 proteins as immunotherapy for cervical cancer.  Lancet  347:1523. 
         8. Nimako, M., A. N. Fiander, G. W. Wilkinson, L. K. Borysiewicz, and S. Man. 1997. Human papillomavirus-specific cytotoxic T lymphocytes in patients with cervical intraepithelial neoplasia grade III.  Cancer Res  57:4855. 
         9. Evans. E. M., S. Man, A. S. Evans, and L. K. Borysiewicz. 1997. Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic T-lymphocytes.  Cancer Res  57:2943. 
         10. Youde, S. J., P. R. Dunbar, E. M. Evans, A. N. Fiander, L. K. Borysiewicz, V. Cerundolo, and S. Man. 2000. Use of fluorogenic histocompatibility leukocyte antigen-A*0201/HPV 16 E7 peptide complexes to isolate rare human cytotoxic T-lymphocyte-recognizing endogenous human papillomavirus antigens.  Cancer Res  60:365. 
         11. Frazer, I. H., R. Thomas, J. Zhou, G. R. Leggatt, L. Dunn, N. McMillan, R. W. Tindle, L. Filgueira, P. Manders, P. Barnard, and M. Sharkey. 1999. Potential strategies utilised by papillomavirus to evade host immunity.  Immunological Reviews  168:131. 
         12. Khammanivong, V., X. S. Liu, W. J. Liu, S. J. Rodda, G. R. Leggatt, R. W. Tindle, I. H. Frazer, and G. J. Fernando. 2003. Paucity of functional CTL epitopes in the E7 oncoprotein of cervical cancer associated human papillomavirus type 16.  Immunol Cell Biol  81:1. 
         13. Scheffner, M., Munger K, Huibregtse J M, and H. PM. 1992. Targeted degradation of the retinoblastoma protein by human papillomavirus E7-E6 fusion proteins. European Molecular Biology Organisation Journal 11:2425. 
         14. Scheffner, M., B. A. Werness, J. M. Huigbretse, A. J. Levine, and P. M. Howley. 1990. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53.  Cell  63:1129. 
         15. Higashitsuji, H. K. Itoh, T. Nagao, S. Dawson., K. Nonoguchi, T. Kido, R. J. Mayer, S. Arii, and J. Fujita. 2000. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas.  Nature Medicine  6:96. 
         16. Rongcun, Y., F. Salazar-Onfray, J. Charo, K. Malmberg, K. Evrin, H. Maes, K. Kono, C. Hising, M. Petersson, O. Larsson, L. Lan, E. Appella, A. Sette, E. Celis, and R. Kiessling. 1999. Identification of New HER2/neu-Derived Peptide Epitopes That Can Elicit Specific CTL Against Autologous and Allogeneic Carcinomas and Melanomas 1 . The Journal of Immunology:  163:1037-1044. 
         17. Vonderheide, R. H., W. C. Hahn, J. L. Schultze, and L. M. Nadler. 1999. The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes.  Immunity  10:673. 
         18. Berezutskaya, E., and S. Bagchi. 1997. The human papillomavirus E7 oncoprotein functionally interacts with the S4 subunit of the 26 S proteasome  J Biol Chem  272:30135. 
         19. Boyer, S. N., D. E. Wazer, and V. Band. 1996. E7 protein of human papilloma virus 16 induces degradation of retinoblastoma protein through the ubiquitin proteasome pathway.  Cancer research  56:4620. 
         20. Michalek, M. T., E. P. Grant, C. Gramm, A. L. Goldberg, and K. L. Rock. 1993. A role for the ubiquitin-dependent proteolytic pathway in MHC class I-restricted antigen presentation.  Nature  363:552. 
         21. Cerundolo, V., A. Benham, V. Braud, S. Mukherjee, K. Gould, B. Macino, J. Neefjes, and A. Townsend. 1997. The proteasome-specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human and murine cells.  Eur J Immunol  27:336. 
         22. Vierboom, M., S. Zwaveling, G. Bos, M. Ooms, G. Krietemeijer, C. Melief, and R. Offring a. 2000. High Steady-State Levels of p53 Are Not a Prerequisite for Tumor Eradication by Wild-Type p53-specific Cytotoxic T Lymphocytes.  Cancer Research  60:5508-5513. 
         23. Vierboom, M. P., H. W. Nijman, R. Offring a, E. I. van der Voort, T. van Hall, L. van den Broek, G. J. Fleuren, P. Kenemans, W. M. Kast, and C. J. Melief. 1997. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.  Journal of Experimental Medicine  186:695. 
         24. Kao, W. H., S. L. Beaudenon, A. L. Talis, J. M. Huibregtse, and P. M. Howley. 2000. Human Papillomavirus Type 16 E6 Induces Self-Ubiquitination of the E6AP Ubiquitin-Protein Ligase.  J. Virol.  74:6408. 
         25. Gross-Mesilaty, S., E. Reinstein, B. Bercovich, K. E. Tobias, A. L. 
         Schwartz, C. Kahana, and A. Ciechanover. 1998. Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway.  Proceedings of the National Academy of Sciences of the United States of America  95:8058. 
         26. Nakagawa, S., and J. M. Huibregtse. 2000. Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase.  Mol Cell Biol  20:8244. 
         27. Kuhne, C., and L. Banks. 1998. E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box.  J Biol Chem  273:34302. 
         28. Glaunsinger, B. A., S. S. Lee, M. Thomas, L. Banks, and R. Javier. 2000. Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins.  Onicogene  19:5270. 
         29. Gao, Q., L. Singh, A. Kumar, S. Srinivasan, D. E. Wazer, and V. Band. 2001. Human papillomavirus type 16 E6-induced degradation of E6TP1 correlates with its ability to immortalize human mammary epithelial cells.  J Virol  75:4459. 
         30. Pim, D., M. Thomas, R. Javier, D. Gardiol, and L. Banks. 2000. HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase  Oncogene  19:719. 
         31. Thomas, M., and L. Banks. 1998. Inhibition of Bak-induced apoptosis by HPV-18 E6.  Oncogene  17:2943. 
         32. Lee, S., B. Glaunsinger, F. Mantovani, L. Banks, and R. Javier. 2000. Multi-PDZ Domain Protein MUPP1 Is a Cellular Target for both Adenovirus E4-ORF1 and High-Risk Papillomavirus Type 18 E6 Oncoproteins.  Journal of Virology  74:9680-9693. 
         33. Srivenugopal, K. S., and F. Ali-Osman. 2002. The DNA repair protein, O(6)-Methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein.  Oncogene  21:5940. 
         34. Thomas, M., R. Laura, K. Hepner, E. Guccione, C. Sawyers, L. Lasky, and L. Banks. 2002. Oncogenic human papillomavirus E6 proteins target the MAGI-2 and MAGI-3 proteins for degradation. Oncogene 21:5088. 
         35. Lu, Z., X. Hu, Y. Li, L. Zheng, Y. Zhou, H. Jiang, T. Ning, Z. Basang, C. Zhang, and Y. Ke. 2004. Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin.  J Biol Chem In press.    
         36. Parker, K. C., M. A. Bednarek, L. K. Hull, U. Utz, B. Cunningham, H. J. Zweerink, W. E. Biddison, and J. E. Coligan. 1992. Sequence motifs important for peptide binding to the human MHC class I molecule, HLA-A2 . Journal of Immunology  149:3580. 
         37. Engelhard, V. H. 1994. Structure of peptides associated with MHC class I molecules.  Current Opinion in Immunology  6:13. 
         38. Ellis, J. R., P. J. Keating, J. Baird, E. F. Hounsell, D. V. Renouf, M. Rowe, D. Hopkins, M. F. Duggan-Keen, J. S. Bartholomew, L. S. Young, and P. L. Stern. 1995. The association of an HPV16 oncogene variant with HLA-B7 has implications for vaccine design in cervical cancer.  Nature Medicine  1:464. 
         39. Faulkner, L., L. K. Borysiewicz, and S. Man. 1998. The use of human leucocyte antigen class I transgenic mice to investigate human immune function.  J Immunol Methods  221:1. 
         40. Dunbar, P., J. Chen, D. Chao, N. Rust, H. Teisserenc, G. Ogg, P. Romero, P. Weynants, and V. Cerundolo. 1999. Rapid cloning of tumour specific CTL suitable for adoptive immunotherapy of melanoma.  Journal of Immunology  162:6959. 
         41. Rooney, C. Mh, C. A. Smith, C. Y. C. Ng, S. K. Loftin, J. W. Sixbey, Y. Gan, D. K. Srivastava, L. C. Bowman, R. A. Krance, M. K. Brenner, and H. E. Heslop. 1998. Infusion of cytotoxic T cells for the prevention and treatment of epstein-barr virus-induced lymphoma in allogeneic transplant recipients  Blood  92:1549. 
         42. Stanislawski, T., R. H. Voss, C. Lotz, E. Sadovnikova, R. A. Willemsen, J. Kuball, T. Ruppert, R. L. Bolhuis, C. J. Melief, C. Huber, H. J. Stauss, and M. Theobaid. 2001. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.  Nat Immunol  2:962. 
         43. Shah, K. V. 1998. Do human papillomavirus infections cause oral cancer?  J Natl Cancer Inst  90:1585. 
         44. Shamanin, V., H. zur Hausen, D. Layergne, C. M. Proby, I. M. Leigh, C. 
         Neumann, H. Hamm, M. Goos, U.-F. Haustein, E. G. Jung, G. Plewig, H. Wolff, and E.-M. de Villiers. 1996. Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients.  Journal of the National Cancer Institute  88:802. 
         45. Kiviat, N. B. 1999, Papillomaviruses in non-melanoma skin cancer: epidemiological aspects.  Semin Cancer Biol  9.:397. 
         46. Man, S. and A. Fiander. 2001. Immunology of human papillomavirus infection in lower genital tract neoplasia.  Best Pract Res Clon Obstet Gynaecol  15:701. 
         47. Palefsky, J. M. 1997. Cutaneous and genital HPV-associated lesions in HIV-infected patients. Clin Dermatol 15:439. 
         48. De Luca, A., A. Baldi, V. Esposito, C. M. Howard, L. Bagella, P. Rizzo, M. Caputi, H. I. Pass, G. G. Giordano, F. Baldi, M. Carbone, and A. Giordano. 1997. The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas  Nature Medicine  3:913. 
         49. Li, B., and Q. P. Dou. 2000. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression.  Proc Natt Acad Sci USA  97:3850. 
         50. Pittet, M. J., Valmori, D., Dunbar, P. R., Speiser, D. E., Linard, D., Lejeune, F., Fleischhauer, K., Cerundolo, V., Cerottini, J. C., and Romero, P. 1999. High Frequencies of Naive Melan-A/MART-1-specific CD8(+) T Cells in a Large Proportion of Human. Histocompatibility Leukocyte Antigen (HLA)-A2 Individuals.  Journal of Experimental Medicine  190:705-716.