Abstract:
This invention relates to a DNA coding for a peptide of a papilloma virus major capsid protein. Moreover, this invention deals with a papilloma virus genome containing such a DNA. Furthermore, this invention concerns proteins coded by the papilloma virus genome and virus-like particles as well as antibodies directed thereagainst and the use thereof for diagnosis, treatment and vaccination.

Description:
[0001]    This is a national phase filing of the Application No. PCT/DE96/01369, which was filed with the Patent Corporation Treaty on Jul. 19, 1996, and is entitled to priority of the German Patent Application P 195 26 386.3, filed Jul. 19, 1995. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    This invention relates to a DNA coding for a peptide of a papilloma virus major capsid protein. Moreover, this invention deals with a papilloma virus genome containing such a DNA. In addition, this invention concerns proteins coded by the papilloma virus genome and virus-like particles as well as antibodies directed against them and their use for diagnosis, treatment and vaccination.  
         BACKGROUND OF THE INVENTION  
         [0003]    It is known that papilloma viruses infect the epithelium of human beings and animals. Human papilloma viruses (hereinafter referred to as HP viruses) are found in benign epithelial neoplasms, e.g warts, condylomas in the genital zone, and malignant epithelial neoplasms, e.g carcinomas of the skin and the uterus. Zur Hausen, 1989,  Cancer Research  49:4677-4681. HP viruses are also considered for the growth of malignant tumors in the respiratory tract. Zur Hausen, 1976,  Cancer Research  36:530. Besides, HP viruses are considered at least jointly responsible for the growth of squamous carcinomas of the lung. Syrjänen, 1980,  Lung  158:131-142.  
           [0004]    Papilloma viruses have an icosahedral capsid without envelope in which a circular, double-stranded DNA molecule of about 7900 bp is present. The capsid comprises a major capsid protein (L1) and a minor capsid protein (L2). Both proteins, coexpressed or L1 expressed alone, result in vitro in the formation of virus-like particles Kirnbauer et al., 1993,  Journal of Virology  67:6929-6936.  
           [0005]    Papilloma viruses cannot be proliferated in monolayer cell culture. Therefore, their characterization is extremely difficult, the detection of papilloma viruses already creating considerable problems. This applies especially to papilloma viruses in carcinomas of the skin. A reliable detection thereof and thus well-calculated steps taken thereagainst are not possible by now.  
           [0006]    Thus, it is the object of the present invention to provide a product by which papilloma viruses can be detected, particularly in carcinomas of the skin. Furthermore, a product should be provided to be able to take therapeutic steps against these papilloma viruses.  
         SUMMARY OF THE INVENTION  
         [0007]    This invention relates to a DNA coding for a peptide of a papilloma virus major capsid protein. Moreover, this invention deals with a papilloma virus genome containing such a DNA. Furthermore, this invention concerns proteins coded by the papilloma virus genome and virus-like particles as well as antibodies directed thereagainst and the use thereof for diagnosis, treatment and vaccination. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]    [0008]FIG. 1 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS19-6 with DSM (Deutsche Sammlung von Mikroorganismen und Zellkulturen [German-type collection of micro-organisms and cell cultures]) under DSM 10104 on Jul. 11, 1995.  
         [0009]    [0009]FIG. 2 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS200-1 with DSM under DSM 10096 on Jul. 11, 1995.  
         [0010]    [0010]FIG. 3 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS201-1 with DSM under DSM 10097 on Jul. 11, 1995.  
         [0011]    [0011]FIG. 4 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS202-8 with DSM under DSM 10098 on Jul. 11, 1995.  
         [0012]    [0012]FIG. 5 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS203-2 with DSM under DSM 10099 on Jul. 11, 1995.  
         [0013]    [0013]FIG. 6 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS204-4 with DSM under DSM 10100 on Jul. 11, 1995.  
         [0014]    [0014]FIG. 7 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS205-1 with DSM under DSM 10101 on Jul. 11, 1995.  
         [0015]    [0015]FIG. 8 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS206-2 with DSM under DSM 10109 on Jul. 13, 1995.  
         [0016]    [0016]FIG. 9 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS207-22 with DSM under DSM 10102 on Jul. 11, 1995.  
         [0017]    [0017]FIG. 10 shows the base sequence and the amino acid sequence, derived therefrom, of a DNA coding for a peptide of L1 of a papilloma virus. This DNA was deposited as plasmid VS208-1 with DSM under DSM 10103 on Jul. 11, 1995. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0018]    It is the object of the present invention to provide a product by which papilloma viruses can be detected, particularly in carcinomas of the skin. Furthermore, a product is provided which enables to take therapeutic steps against these papilloma viruses.  
         [0019]    Accordingly, the subject matter of the invention relates to a DNA coding for a peptide of a papilloma virus major capsid protein (L1), the peptide comprising the amino acid sequence of FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG. 7, FIG. 8, FIG. 9 or FIG. 10 or an amino acid sequence differing therefrom by one or more amino acids.  
         [0020]    A further subject matter of the invention relates to a DNA coding for a peptide of a papilloma virus major capsid protein, the DNA comprising the base sequence of FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG. 7, FIG. 8, FIG. 9 or FIG. 10 or a base sequence differing therefrom by one or more base pairs.  
         [0021]    The above DNA has the following sequence homology with respect to known papilloma viruses:  
                                                       DNA of FIG. 1:   69.1% with respect to HP virus 65           DNA of FIG. 2:   80.7% with respect to HP virus 24           DNA of FIG. 3:   69.4% with respect to HP virus 48           DNA of FIG. 4:   66.3% with respect to HP virus 48           DNA of FIG. 5:   66.9% with respect to HP virus 65           DNA of FIG. 6:   66.4% with respect to HP virus 65           DNA of FIG. 7:   69.1% with respect to HP virus 4           DNA of FIG. 8:   68.7% with respect to HP virus 48           DNA of FIG. 9:   76.6% with respect to HP virus 48           DNA of FIG. 10:   81.8% with respect to HP virus 68                      
 
         [0022]    According to the invention, the above DNA can be present in a vector and expression vector, respectively. A person skilled in the art is familiar with examples thereof. In the case of an expression vector for  E. coli,  these are e.g pGEMEX, pUC derivatives, pGEM-T and pGEX-2T. For the expression in yeast e.g. pY100 and Ycpadl have to be mentioned, while for the expression in animal cells e.g. pKCR, pEF-BOS, cDM8 and pCEV4 have to be indicated.  
         [0023]    The person skilled in the art knows suitable cells to express the above DNA present in an expression vector. Examples of such cells comprise the  E. coli  strains HB101, DH1, x1776, JM101, JM 109, and XL1-Blue, the yeast strain  Saccharomyces cerevisiae  and the animal cells L, NH-3T3, FM3A, CHO, COS, Vero, and HeLa.  
         [0024]    The person skilled in the art knows in which way the above DNA has to be inserted in an expression vector. He is also familiar with the fact that the above DNA can be inserted in connection with a DNA coding for another protein and peptide, respectively, so that the above DNA can be expressed in the form of a fusion protein.  
         [0025]    A further subject matter of the invention relates to a papilloma virus genome which comprises the above DNA. The expression “papilloma virus genome” also comprises an incomplete genome, i.e. fragments of a papilloma virus genome, which comprise the above DNA. This may be e.g a DNA coding for L1 or a portion thereof.  
         [0026]    A common process can be used for the provision of the above papilloma virus genome, which comprises the following processing steps:  
         [0027]    (a) isolation of the total DNA from a biopsy of epithelial neoplasm,  
         [0028]    (b) hybridization of the total DNA of (a) with the above DNA so as to detect a papilloma virus genome included in the total DNA of (a), and  
         [0029]    (c) cloning of the total DNA of (a) containing the papilloma virus genome, in a vector and optionally subcloning the resulting clone, all processing steps originating from common DNA recombination technique.  
         [0030]    As far as the isolation, hybridization and cloning of cell DNA is concerned, reference is made by way of supplement to Sambrook et al.,  Molecular Cloning A Laboratory Manual,  second edition, Cold Spring Harbor Laboratory (1989).  
         [0031]    The expression “epithelial neoplasm” comprises any neoplasms of epithelium in man and animal. Examples of such neoplasms are warts, condylomas in the genital zone and carcinomas of the skin. The latter are used preferably to isolate the above papilloma virus genome.  
         [0032]    The expression “vector” comprises any vectors suitable for cloning chromosomal DNA and extrachromosomal DNA, respectively. Examples of such vectors are cosmids such as pWE15 and Super Cos1, and phages such as λ-phages, e.g. λZAP expression vector, λZAPII vector and λgt10 vector. In the present case, λ-phages are used preferably. The above vectors are known and obtainable from the company of Stratagene.  
         [0033]    Papilloma virus genomes according to the invention may be present in integrated form in chromosomal DNA or in extrachromosomal fashion. The person skilled in the art is familiar with processes serving the clarification thereof. He also knows processes serving for finding out the optimum restriction enzymes for cloning the papilloma virus genomes. He will orient himself by genomes of known papilloma viruses. In particular, the person skilled in the art will pay corresponding attention to the above-mentioned HP viruses.  
         [0034]    The provision of a papilloma virus genome referred to as VS19-6 is described by way of example. For this purpose, the total DNA is isolated from a biopsy of a squamous cell carcinoma, cleaved by BamHI and separated eletrophoretically in an agarose gel. The agarose gel is then subjected to a blotting method so as to transfer the DNA to a nitrocellulose membrane. It is inserted in a hybridization method in which the DNA of FIG. 1 is used as labeled sample, optionally in combination with a DNA of HP virus 65. Hybridization with the papilloma virus DNA present in the total DNA is obtained.  
         [0035]    Moreover, the above total DNA cleaved by BamHI is cloned in a λ-phage. The corresponding clones, i.e. the clones containing the papilloma virus DNA are identified by hybridization with the DNA of FIG. 1, optionally in combination with a DNA of the HP virus 65. The insert of these clones is then subjected to a further cloning in a plasmid vector so as to obtain a clone which contains the papilloma virus genome VS19-6-G. The genome is confirmed by sequencing.  
         [0036]    Further papilloma virus genomes are provided analogously. They are designated in accordance with the DNAs used for their provision, namely by: VS200-1-G, VS201-1-G, VS202-8-G, VS203-2-G, VS204-4-G, VS205-1-G, VS206-2-G, VS207-22-G and VS208-1-G, respectively.  
         [0037]    A further subject matter of the invention relates to a protein which is coded by the above papilloma virus genome. Such a protein is e.g. a major capsid protein (L1) or a minor capsid protein (L2). An above protein is prepared as usual. The preparation of L1 and L2, respectively, of the papilloma virus genome VS19-6-G is described by way of example. For this purpose, the HP virus 65 related to the DNA of FIG. 1 is used. The full sequence and the position of individual DNA regions coding for proteins are known in connection therewith. These DNAs are identified on the papilloma virus genome VS19-6-G by parallel restriction cleavages of both genomes and subsequent hybridization with various fragments concerning the DNA encoding L1 and L2, respectively. They are confirmed by sequencing. The DNA coding for L1 is referred to as VS19-6-G-L1 DNA and the DNA coding for L2 is referred to as VS19-6-G-L2 DNA.  
         [0038]    Furthermore, the DNA coding for L1 and L2, respectively, is inserted in an expression vector. Examples thereof are mentioned above for  E. coli,  yeast and animal cells. In this connection, reference is made to the vector pGEX-2T as regards the expression in  E. coli  by way of supplement. Kimbauer et al., supra. Having inserted the VS19-6-G-L1 DNA and VS19-6-G-L2 DNA, one obtains pGEX-2T-VS19-6-G-L1 and pGEX-2T-VS19-6-G-L2, respectively. After transforming  E. coli,  these expression vectors express a glutathione S transferase L1 fusion protein and glutathione S transferase L2 fusion protein, respectively. The proteins are purified as usual.  
         [0039]    The bacculovirus system and vaccinia virus system, respectively, is mentioned for a further expression of the above DNA encoding L1 and L2, respectively. Expression vectors usable for this purpose are e.g. pEV mod. and pSynwtVI for the bacculovirus system. Kirnbauer et al., supra. Especially vectors with the vaccinia virus “early” (p7.5 k) promoter and “late” (Psynth, p11K) promoter, respectively, have to be mentioned for the vaccinia virus system. Hagensee et al., 1993,  Journal of Virology  67:315-322. The bacculovirus system is preferred in the present case. Having inserted the above DNA encoding L1 and L2, respectively, in pEV mod., one obtains pEVmod.-VS19-6-G-L1 and pEVmod.-VS19-6-G-L2, respectively.  
         [0040]    The former expression vector as such or both expression vectors jointly lead to the formation of virus-like particles after infection of SF-9 insect cells. In the former case, such a particle comprises an L1 protein, while in the latter case, it contains an L2 protein in addition to an L1 protein.  
         [0041]    A virus-like particle of the latter case is also obtained by inserting the above VS 19-6-G-L1 and VSI9-6-G-L2 DNAs jointly in the expression vector pSynwtVI and using the resulting pSynwtVI-VS19-6-G-L1/L2 for the infection of SF-9 insect cells. The above virus-like particles are purified as usual. They also represent a subject matter of the invention.  
         [0042]    A further subject matter of the invention relates to an antibody directed against an above protein and virus-like particle, respectively. The preparation thereof is made as usual. It is described by way of example for the preparation of an antibody which is directed against a virus-like particle comprising L1 of VS19-6-G. For this purpose, the virus-like particle is injected subcutaneously into BALB/c mice. This injection is repeated at intervals of 3 weeks each. About 2 weeks after the last injection, the serum containing the antibody is isolated and tested as usual.  
         [0043]    In a preferred embodiment, the antibody is a monoclonal antibody. For its preparation, spleen cells are removed from the mice after the above fourth injection and fused with myeloma cells as usual. The further cloning also takes place according to known methods.  
         [0044]    By means of the present invention, it is possible to detect papilloma viruses, particularly in carcinomas of the skin. For this purpose, the DNA according to the invention can be used as such or when comprised by a further DNA. The latter may also be a papilloma virus genome or a portion thereof.  
         [0045]    The present invention also enables the provision of formerly unknown papilloma viruses. They are found especially in carcinomas of the skin. In addition, the invention supplies proteins and virus-like particles which originate from these papilloma viruses. Moreover, antibodies are provided which are directed against these proteins and particles, respectively.  
         [0046]    The present invention also enables to take diagnostic and therapeutic steps in the case of papilloma virus diseases. Moreover, it supplies the possibility of building up a vaccine against papilloma virus infections. Thus, the present invention represents a break-through in the field of papilloma virus research.  
         [0047]    The below examples explain the invention in more detail. The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.  
       EXAMPLES  
     A. Example 1  
     Identification of the Papilloma Virus Genome VS19-6-G  
       [0048]    The total DNA is isolated from a biopsy of a squamous cell carcinoma of an immuno-suppressed person. 10 μg of this DNA are cleaved by the restriction enzyme BamHI and separated electrophoretically in a 0.5% agarose gel. At the same time, 10 μg of the above DNA, which was not cleaved, is also separated. The agarose gel is subjected to a blotting method so as to transfer the DNA from the agarose gel to a nitrocellulose membrane. It is employed in a hybridization method in which the above DNA of FIG. 1 is used in combination with the HP virus-65 DNA as  32 P-labeled sample. Hybridization with the blotted DNA is obtained.  
         [0049]    The person skilled in the field of DNA recombination technique is familiar with the above methods. Reference is made to Sambrook et al., supra, by way of supplement.  
       Example 2  
     Cloning of the Papilloma Virus Genome VS19-6-G.  
       [0050]    The biopsy DNA obtained from Example 1 is cleaved by the restriction enzyme BamHI. The resulting fragments are used in a ligase reaction in which the dephosphorylated vector λZAP express cleaved by BamHI is also present. The resulting recombinant DNA molecules are packed in bacteriophages, and they are used for infecting bacteria. For these processing steps, the ZAP express vector kit offered by the company of Stratagene is used. The resulting phage plaques are then subjected to a hybridization process which uses the  32 P-labeled DNA of FIG. 1 employed in Example 1 in combination with  32 P-labeled HP virus-65 DNA. Hybridization with corresponding phage plaques is obtained. The BamHI fragments of VS19-6-G are isolated therefrom and used in a further ligase reaction together with a BamHI-cleaved, dephosphorylated plasmid vector, pBluescript. The resulting recombinant DNA molecules are used for transforming bacteria,  E. coli  XL 1-Blue. By restriction cleavages and hybridization with the above DNA samples, respectively, a bacterial clone containing the papilloma virus genome VS19-6-G is identified. The plasmid of this bacterial clone is referred to as pBlue-VS19-6-G.  
         [0051]    All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.  
     
       
       
         1 
         
           
             30  
           
           
             1  
             419  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(417)  
             
           
            1 

gga tcc atg cag gat ggt gac atg tgt gat ata gga ttc gga gct tgc       48 
Gly Ser Met Gln Asp Gly Asp Met Cys Asp Ile Gly Phe Gly Ala Cys 
 1               5                   10                  15 

aat ttc agg gca ttt cag caa gat agg tca ggt gtt cct tta gat ata       96 
Asn Phe Arg Ala Phe Gln Gln Asp Arg Ser Gly Val Pro Leu Asp Ile 
             20                  25                  30 

gta gat agt act tgc aag tat cca gac ttt ttg aaa atg aca aaa gac      144 
Val Asp Ser Thr Cys Lys Tyr Pro Asp Phe Leu Lys Met Thr Lys Asp 
         35                  40                  45 

aag tat ggt gat gaa tgc ttc ttt ttt ggt cgt cga gag cag ttg tat      192 
Lys Tyr Gly Asp Glu Cys Phe Phe Phe Gly Arg Arg Glu Gln Leu Tyr 
     50                  55                  60 

gca agg cat tat ttt acc aga gca ggc aca ata ggt gat tct att cca      240 
Ala Arg His Tyr Phe Thr Arg Ala Gly Thr Ile Gly Asp Ser Ile Pro 
 65                  70                  75                  80 

acg cca tat cag gaa tct gaa ttt tac aga tct cca cag gat agc cag      288 
Thr Pro Tyr Gln Glu Ser Glu Phe Tyr Arg Ser Pro Gln Asp Ser Gln 
                 85                  90                  95 

gct cag aat aat gtg gat tct cac att tat gta gcc act cct agt ggt      336 
Ala Gln Asn Asn Val Asp Ser His Ile Tyr Val Ala Thr Pro Ser Gly 
            100                 105                 110 

tct tta act agc agt gat gct cag ctg ttt aac aga cct tat tgg ctc      384 
Ser Leu Thr Ser Ser Asp Ala Gln Leu Phe Asn Arg Pro Tyr Trp Leu 
        115                 120                 125 

caa aat gct caa ggt acc aat aac gga atg gat cc                       419 
Gln Asn Ala Gln Gly Thr Asn Asn Gly Met Asp 
    130                 135 

 
           
             2  
             139  
             PRT  
             Papilloma virus  
           
            2 

Gly Ser Met Gln Asp Gly Asp Met Cys Asp Ile Gly Phe Gly Ala Cys 
 1               5                  10                  15 

Asn Phe Arg Ala Phe Gln Gln Asp Arg Ser Gly Val Pro Leu Asp Ile 
            20                  25                  30 

Val Asp Ser Thr Cys Lys Tyr Pro Asp Phe Leu Lys Met Thr Lys Asp 
        35                  40                  45 

Lys Tyr Gly Asp Glu Cys Phe Phe Phe Gly Arg Arg Glu Gln Leu Tyr 
    50                  55                  60 

Ala Arg His Tyr Phe Thr Arg Ala Gly Thr Ile Gly Asp Ser Ile Pro 
65                  70                  75                  80 

Thr Pro Tyr Gln Glu Ser Glu Phe Tyr Arg Ser Pro Gln Asp Ser Gln 
                85                  90                  95 

Ala Gln Asn Asn Val Asp Ser His Ile Tyr Val Ala Thr Pro Ser Gly 
            100                 105                 110 

Ser Leu Thr Ser Ser Asp Ala Gln Leu Phe Asn Arg Pro Tyr Trp Leu 
        115                 120                 125 

Gln Asn Ala Gln Gly Thr Asn Asn Gly Met Asp 
    130                 135 

 
           
             3  
             419  
             DNA  
             Papilloma virus  
           
            3 

ggatccattc cgttattggt accttgagca ttttggagcc aataaggtct gttaaacagc     60 

tgagcatcac tgctagttaa agaaccacta ggagtggcta cataaatgtg agaatccaca    120 

ttattctgag cctggctatc ctgtggagat ctgtaaaatt cagattcctg atatggcgtt    180 

ggaatagaat cacctattgt gcctgctctg gtaaaataat gccttgcata caactgctct    240 

cgacgaccaa aaaagaagca ttcatcacca tacttgtctt ttgtcatttt caaaaagtct    300 

ggatacttgc aagtactatc tactatatct aaaggaacac ctgacctatc ttgctgaaat    360 

gccctgaaat tgcaagctcc gaatcctata tcacacatgt caccatcctg catggatcc     419 

 
           
             4  
             434  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(432)  
             
           
            4 

gga tcc atg gag gac ggt gag atg gca gac ata gga tat ggt aat ctt       48 
Gly Ser Met Glu Asp Gly Glu Met Ala Asp Ile Gly Tyr Gly Asn Leu 
 1               5                   10                  15 

aat ttt aaa gct tta cag gaa aat agg cct gat gtt agt ctt gat att       96 
Asn Phe Lys Ala Leu Gln Glu Asn Arg Pro Asp Val Ser Leu Asp Ile 
             20                  25                  30 

gtc aat gaa acc tgc aaa tat cca gat ttt ttg aag atg caa aat gat      144 
Val Asn Glu Thr Cys Lys Tyr Pro Asp Phe Leu Lys Met Gln Asn Asp 
         35                  40                  45 

gtt tat gga gac tcc tgt ttc ttt ttt gct cgt aga gag caa tgt tat      192 
Val Tyr Gly Asp Ser Cys Phe Phe Phe Ala Arg Arg Glu Gln Cys Tyr 
     50                  55                  60 

gcc aga cac ttt ttt gta aga ggt ggc aac gta ggg gat gac att cct      240 
Ala Arg His Phe Phe Val Arg Gly Gly Asn Val Gly Asp Asp Ile Pro 
 65                  70                  75                  80 

ggt gaa caa ata gac gca ggc aca tat aaa aat gat ttt tac att cca      288 
Gly Glu Gln Ile Asp Ala Gly Thr Tyr Lys Asn Asp Phe Tyr Ile Pro 
                 85                  90                  95 

gga gca tca ggt cag aca caa aat aaa ata ggt aac tcc atg tat ttc      336 
Gly Ala Ser Gly Gln Thr Gln Asn Lys Ile Gly Asn Ser Met Tyr Phe 
            100                 105                 110 

cca aca gtt agt ggc tca tta gtg tct agt gat gct cag ctg ttt aat      384 
Pro Thr Val Ser Gly Ser Leu Val Ser Ser Asp Ala Gln Leu Phe Asn 
        115                 120                 125 

agg ccc tac tgg ctc caa cgc gca cag ggc cac aac aac ggc gtg gat      432 
Arg Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn Gly Val Asp 
    130                 135                 140 

cc                                                                   434 

 
           
             5  
             144  
             PRT  
             Papilloma virus  
           
            5 

Gly Ser Met Glu Asp Gly Glu Met Ala Asp Ile Gly Tyr Gly Asn Leu 
 1               5                  10                  15 

Asn Phe Lys Ala Leu Gln Glu Asn Arg Pro Asp Val Ser Leu Asp Ile 
            20                  25                  30 

Val Asn Glu Thr Cys Lys Tyr Pro Asp Phe Leu Lys Met Gln Asn Asp 
        35                  40                  45 

Val Tyr Gly Asp Ser Cys Phe Phe Phe Ala Arg Arg Glu Gln Cys Tyr 
    50                  55                  60 

Ala Arg His Phe Phe Val Arg Gly Gly Asn Val Gly Asp Asp Ile Pro 
65                  70                  75                  80 

Gly Glu Gln Ile Asp Ala Gly Thr Tyr Lys Asn Asp Phe Tyr Ile Pro 
                85                  90                  95 

Gly Ala Ser Gly Gln Thr Gln Asn Lys Ile Gly Asn Ser Met Tyr Phe 
            100                 105                 110 

Pro Thr Val Ser Gly Ser Leu Val Ser Ser Asp Ala Gln Leu Phe Asn 
        115                 120                 125 

Arg Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn Gly Val Asp 
    130                 135                 140 

 
           
             6  
             434  
             DNA  
             Papilloma virus  
           
            6 

ggatccacgc cgttgttgtg gccctgtgcg cgttggagcc agtagggcct attaaacagc     60 

tgagcatcac tagacactaa tgagccacta actgttggga aatacatgga gttacctatt    120 

ttattttgtg tctgacctga tgctcctgga atgtaaaaat catttttata tgtgcctgcg    180 

tctatttgtt caccaggaat gtcatcccct acgttgccac ctcttacaaa aaagtgtctg    240 

gcataacatt gctctctacg agcaaaaaag aaacaggagt ctccataaac atcattttgc    300 

atcttcaaaa aatctggata tttgcaggtt tcattgacaa tatcaagact aacatcaggc    360 

ctattttcct gtaaagcttt aaaattaaga ttaccatatc ctatgtctgc catctcaccg    420 

tcctccatgg atcc                                                      434 

 
           
             7  
             410  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(408)  
             
           
            7 

gga tcc cta gag gat ggt gat atg ggt gat ata gga ttt ggg cat gct       48 
Gly Ser Leu Glu Asp Gly Asp Met Gly Asp Ile Gly Phe Gly His Ala 
 1               5                   10                  15 

aat ttt agc cgt tta caa gaa gat aaa gca ggt gtg cca tta gaa tta       96 
Asn Phe Ser Arg Leu Gln Glu Asp Lys Ala Gly Val Pro Leu Glu Leu 
             20                  25                  30 

gtg gac act ttt agt ata tgg cct gac ttt tta cgc atg acc agt gat      144 
Val Asp Thr Phe Ser Ile Trp Pro Asp Phe Leu Arg Met Thr Ser Asp 
         35                  40                  45 

ata tat gga gat gct gtg ttt ttt tgg gga aag cga gaa cat atg ttt      192 
Ile Tyr Gly Asp Ala Val Phe Phe Trp Gly Lys Arg Glu His Met Phe 
     50                  55                  60 

gcc aga cat tta tgg gca aga gct gga act atg ggc gac gct att cca      240 
Ala Arg His Leu Trp Ala Arg Ala Gly Thr Met Gly Asp Ala Ile Pro 
 65                  70                  75                  80 

gat aat aat gca gag ttt ttt ctg cat ccc aat ggt gca cct caa aat      288 
Asp Asn Asn Ala Glu Phe Phe Leu His Pro Asn Gly Ala Pro Gln Asn 
                 85                  90                  95 

aag tta gcc tca ttt gct tat ttt cca aca cct agt ggt tct ctt aat      336 
Lys Leu Ala Ser Phe Ala Tyr Phe Pro Thr Pro Ser Gly Ser Leu Asn 
            100                 105                 110 

acc agt gat aat caa ttg ttt aat aag ccg tat tgg ttg cga aaa gct      384 
Thr Ser Asp Asn Gln Leu Phe Asn Lys Pro Tyr Trp Leu Arg Lys Ala 
        115                 120                 125 

cag ggc acc aac aat ggg atg gat cc                                   410 
Gln Gly Thr Asn Asn Gly Met Asp 
    130                 135 

 
           
             8  
             136  
             PRT  
             Papilloma virus  
           
            8 

Gly Ser Leu Glu Asp Gly Asp Met Gly Asp Ile Gly Phe Gly His Ala 
 1               5                  10                  15 

Asn Phe Ser Arg Leu Gln Glu Asp Lys Ala Gly Val Pro Leu Glu Leu 
            20                  25                  30 

Val Asp Thr Phe Ser Ile Trp Pro Asp Phe Leu Arg Met Thr Ser Asp 
        35                  40                  45 

Ile Tyr Gly Asp Ala Val Phe Phe Trp Gly Lys Arg Glu His Met Phe 
    50                  55                  60 

Ala Arg His Leu Trp Ala Arg Ala Gly Thr Met Gly Asp Ala Ile Pro 
65                  70                  75                  80 

Asp Asn Asn Ala Glu Phe Phe Leu His Pro Asn Gly Ala Pro Gln Asn 
                85                  90                  95 

Lys Leu Ala Ser Phe Ala Tyr Phe Pro Thr Pro Ser Gly Ser Leu Asn 
            100                 105                 110 

Thr Ser Asp Asn Gln Leu Phe Asn Lys Pro Tyr Trp Leu Arg Lys Ala 
        115                 120                 125 

Gln Gly Thr Asn Asn Gly Met Asp 
    130                 135 

 
           
             9  
             410  
             DNA  
             Papilloma virus  
           
            9 

ggatccatcc cattgttggt gccctgagct tttcgcaacc aatacggctt attaaacaat     60 

tgattatcac tggtattaag agaaccacta ggtgttggaa aataagcaaa tgaggctaac    120 

ttattttgag gtgcaccatt gggatgcaga aaaaactctg cattattatc tggaatagcg    180 

tcgcccatag ttccagctct tgcccataaa tgtctggcaa acatatgttc tcgctttccc    240 

caaaaaaaca cagcatctcc atatatatca ctggtcatgc gtaaaaagtc aggccatata    300 

ctaaaagtgt ccactaattc taatggcaca cctgctttat cttcttgtaa acggctaaaa    360 

ttagcatgcc caaatcctat atcacccata tcaccatcct ctagggatcc               410 

 
           
             10  
             437  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(435)  
             
           
            10 

gga tcc att gag gat gcg gat atg agt gat ata gga ttt gga gct gtg       48 
Gly Ser Ile Glu Asp Ala Asp Met Ser Asp Ile Gly Phe Gly Ala Val 
 1               5                   10                  15 

aat ttt agc act ttc tct gaa agc cgg gct gat gca cct tta gaa tta       96 
Asn Phe Ser Thr Phe Ser Glu Ser Arg Ala Asp Ala Pro Leu Glu Leu 
             20                  25                  30 

atc aat tct att agt aaa tgg cct gat ttt att caa atg tct aag gat      144 
Ile Asn Ser Ile Ser Lys Trp Pro Asp Phe Ile Gln Met Ser Lys Asp 
         35                  40                  45 

att tat ggc gat aga atg ttt ttc ttt gga aaa cgt gag cag atg tat      192 
Ile Tyr Gly Asp Arg Met Phe Phe Phe Gly Lys Arg Glu Gln Met Tyr 
     50                  55                  60 

gca aga cac aca ttt tgt aaa gat ggt gct gtg gga gat gct att cca      240 
Ala Arg His Thr Phe Cys Lys Asp Gly Ala Val Gly Asp Ala Ile Pro 
 65                  70                  75                  80 

gaa aat tta aat aat gat gag gat gtt cat cat agg ttt tta tta aat      288 
Glu Asn Leu Asn Asn Asp Glu Asp Val His His Arg Phe Leu Leu Asn 
                 85                  90                  95 

cct aag cct gac gca cca cca tat tca aac tta gga aac agt act tac      336 
Pro Lys Pro Asp Ala Pro Pro Tyr Ser Asn Leu Gly Asn Ser Thr Tyr 
            100                 105                 110 

ttt cct atg cca agt ggt tca tta gtt agt agt gaa act caa tta ttt      384 
Phe Pro Met Pro Ser Gly Ser Leu Val Ser Ser Glu Thr Gln Leu Phe 
        115                 120                 125 

aac aga cca ttt tgg cta cat cga gca cag ggc acc aat aac ggc atg      432 
Asn Arg Pro Phe Trp Leu His Arg Ala Gln Gly Thr Asn Asn Gly Met 
    130                 135                 140 

gat cc                                                               437 
Asp 
145 

 
           
             11  
             145  
             PRT  
             Papilloma virus  
           
            11 

Gly Ser Ile Glu Asp Ala Asp Met Ser Asp Ile Gly Phe Gly Ala Val 
 1               5                  10                  15 

Asn Phe Ser Thr Phe Ser Glu Ser Arg Ala Asp Ala Pro Leu Glu Leu 
            20                  25                  30 

Ile Asn Ser Ile Ser Lys Trp Pro Asp Phe Ile Gln Met Ser Lys Asp 
        35                  40                  45 

Ile Tyr Gly Asp Arg Met Phe Phe Phe Gly Lys Arg Glu Gln Met Tyr 
    50                  55                  60 

Ala Arg His Thr Phe Cys Lys Asp Gly Ala Val Gly Asp Ala Ile Pro 
65                  70                  75                  80 

Glu Asn Leu Asn Asn Asp Glu Asp Val His His Arg Phe Leu Leu Asn 
                85                  90                  95 

Pro Lys Pro Asp Ala Pro Pro Tyr Ser Asn Leu Gly Asn Ser Thr Tyr 
            100                 105                 110 

Phe Pro Met Pro Ser Gly Ser Leu Val Ser Ser Glu Thr Gln Leu Phe 
        115                 120                 125 

Asn Arg Pro Phe Trp Leu His Arg Ala Gln Gly Thr Asn Asn Gly Met 
    130                 135                 140 

Asp 
145 

 
           
             12  
             437  
             DNA  
             Papilloma virus  
           
            12 

ggatccatgc cgttattggt gccctgtgct cgatgtagcc aaaatggtct gttaaataat     60 

tgagtttcac tactaactaa tgaaccactt ggcataggaa agtaagtact gtttcctaag    120 

tttgaatatg gtggtgcgtc aggcttagga tttaataaaa acctatgatg aacatcctca    180 

tcattattta aattttctgg aatagcatct cccacagcac catctttaca aaatgtgtgt    240 

cttgcataca tctgctcacg ttttccaaag aaaaacattc tatcgccata aatatcctta    300 

gacatttgaa taaaatcagg ccatttacta atagaattga ttaattctaa aggtgcatca    360 

gcccggcttt cagagaaagt gctaaaattc acagctccaa atcctatatc actcatatcc    420 

gcatcctcaa tggatcc                                                   437 

 
           
             13  
             416  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(414)  
             
           
            13 

gga tcc atg gag gat ggt gaa atg ggc gac ata ggc ttt gga gcc ttt       48 
Gly Ser Met Glu Asp Gly Glu Met Gly Asp Ile Gly Phe Gly Ala Phe 
 1               5                   10                  15 

aat ttt aaa gcc cta cag aaa gat cgt gct ggt gtt agt tta gat tta       96 
Asn Phe Lys Ala Leu Gln Lys Asp Arg Ala Gly Val Ser Leu Asp Leu 
             20                  25                  30 

gtt gat aca ttc agt ata tgg cca gac ttt tta aaa atg act aat gat      144 
Val Asp Thr Phe Ser Ile Trp Pro Asp Phe Leu Lys Met Thr Asn Asp 
         35                  40                  45 

ata tat ggt gac agt atc ttt ttt tat ggt aaa aga gaa cag cta ttt      192 
Ile Tyr Gly Asp Ser Ile Phe Phe Tyr Gly Lys Arg Glu Gln Leu Phe 
     50                  55                  60 

agt aga cac ttg tgg gcc cgc gca gga acg gct gga gat gcc att cca      240 
Ser Arg His Leu Trp Ala Arg Ala Gly Thr Ala Gly Asp Ala Ile Pro 
 65                  70                  75                  80 

tct cct gat aac aaa aat cta ata ttt cag ggt gat gat gca gtg cca      288 
Ser Pro Asp Asn Lys Asn Leu Ile Phe Gln Gly Asp Asp Ala Val Pro 
                 85                  90                  95 

caa aag act gct ggg tct ttt act tat ttt agt gcc cct agt ggg tca      336 
Gln Lys Thr Ala Gly Ser Phe Thr Tyr Phe Ser Ala Pro Ser Gly Ser 
            100                 105                 110 

tta aca act agt gat tct cag tta ttt aat agg cca tat tgg tta aga      384 
Leu Thr Thr Ser Asp Ser Gln Leu Phe Asn Arg Pro Tyr Trp Leu Arg 
        115                 120                 125 

aga gct caa ggt acc aac aac ggt gtg gat cc                           416 
Arg Ala Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135 

 
           
             14  
             138  
             PRT  
             Papilloma virus  
           
            14 

Gly Ser Met Glu Asp Gly Glu Met Gly Asp Ile Gly Phe Gly Ala Phe 
 1               5                  10                  15 

Asn Phe Lys Ala Leu Gln Lys Asp Arg Ala Gly Val Ser Leu Asp Leu 
            20                  25                  30 

Val Asp Thr Phe Ser Ile Trp Pro Asp Phe Leu Lys Met Thr Asn Asp 
        35                  40                  45 

Ile Tyr Gly Asp Ser Ile Phe Phe Tyr Gly Lys Arg Glu Gln Leu Phe 
    50                  55                  60 

Ser Arg His Leu Trp Ala Arg Ala Gly Thr Ala Gly Asp Ala Ile Pro 
65                  70                  75                  80 

Ser Pro Asp Asn Lys Asn Leu Ile Phe Gln Gly Asp Asp Ala Val Pro 
                85                  90                  95 

Gln Lys Thr Ala Gly Ser Phe Thr Tyr Phe Ser Ala Pro Ser Gly Ser 
            100                 105                 110 

Leu Thr Thr Ser Asp Ser Gln Leu Phe Asn Arg Pro Tyr Trp Leu Arg 
        115                 120                 125 

Arg Ala Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135 

 
           
             15  
             416  
             DNA  
             Papilloma virus  
           
            15 

ggatccacac cgttgttggt accttgagct cttcttaacc aatatggcct attaaataac     60 

tgagaatcac tagttgttaa tgacccacta ggggcactaa aataagtaaa agacccagca    120 

gtcttttgtg gcactgcatc atcaccctga aatattagat ttttgttatc aggagatgga    180 

atggcatctc cagccgttcc tgcgcgggcc cacaagtgtc tactaaatag ctgttctctt    240 

ttaccataaa aaaagatact gtcaccatat atatcattag tcatttttaa aaagtctggc    300 

catatactga atgtatcaac taaatctaaa ctaacaccag cacgatcttt ctgtagggct    360 

ttaaaattaa aggctccaaa gcctatgtcg cccatttcac catcctccat ggatcc        416 

 
           
             16  
             413  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(411)  
             
           
            16 

gga tcc atg gag gac ggt gag atg agt gat aca ggt ttt ggt gct atg       48 
Gly Ser Met Glu Asp Gly Glu Met Ser Asp Thr Gly Phe Gly Ala Met 
 1               5                   10                  15 

aat ttt gat aat cta tgc gag gac aga gct tca ttt cct tta gac att       96 
Asn Phe Asp Asn Leu Cys Glu Asp Arg Ala Ser Phe Pro Leu Asp Ile 
             20                  25                  30 

ata aat gag acc tcc aag tgg cct gat ttt cta aaa atg aat aaa gat      144 
Ile Asn Glu Thr Ser Lys Trp Pro Asp Phe Leu Lys Met Asn Lys Asp 
         35                  40                  45 

cct tat gga gat cat ata ttt ttc ttt ggt tta cga gag cag tta tat      192 
Pro Tyr Gly Asp His Ile Phe Phe Phe Gly Leu Arg Glu Gln Leu Tyr 
     50                  55                  60 

tcc aga cat cat ggt gct cgg gga gga aaa atg gga gat act att cca      240 
Ser Arg His His Gly Ala Arg Gly Gly Lys Met Gly Asp Thr Ile Pro 
 65                  70                  75                  80 

gaa aat aca gca ggc gaa tat tat tat cct cct act gat ggt gct cag      288 
Glu Asn Thr Ala Gly Glu Tyr Tyr Tyr Pro Pro Thr Asp Gly Ala Gln 
                 85                  90                  95 

caa aat ata ggt tca cat att tat ttc aat act gtt agt gga tct tta      336 
Gln Asn Ile Gly Ser His Ile Tyr Phe Asn Thr Val Ser Gly Ser Leu 
            100                 105                 110 

aca tct tca gaa act cag ata ttt aat agg cca tat ttt tta caa cgt      384 
Thr Ser Ser Glu Thr Gln Ile Phe Asn Arg Pro Tyr Phe Leu Gln Arg 
        115                 120                 125 

gca cag ggc aca aac aac gga gtg gat cc                               413 
Ala Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135 

 
           
             17  
             137  
             PRT  
             Papilloma virus  
           
            17 

Gly Ser Met Glu Asp Gly Glu Met Ser Asp Thr Gly Phe Gly Ala Met 
 1               5                  10                  15 

Asn Phe Asp Asn Leu Cys Glu Asp Arg Ala Ser Phe Pro Leu Asp Ile 
            20                  25                  30 

Ile Asn Glu Thr Ser Lys Trp Pro Asp Phe Leu Lys Met Asn Lys Asp 
        35                  40                  45 

Pro Tyr Gly Asp His Ile Phe Phe Phe Gly Leu Arg Glu Gln Leu Tyr 
    50                  55                  60 

Ser Arg His His Gly Ala Arg Gly Gly Lys Met Gly Asp Thr Ile Pro 
65                  70                  75                  80 

Glu Asn Thr Ala Gly Glu Tyr Tyr Tyr Pro Pro Thr Asp Gly Ala Gln 
                85                  90                  95 

Gln Asn Ile Gly Ser His Ile Tyr Phe Asn Thr Val Ser Gly Ser Leu 
            100                 105                 110 

Thr Ser Ser Glu Thr Gln Ile Phe Asn Arg Pro Tyr Phe Leu Gln Arg 
        115                 120                 125 

Ala Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135 

 
           
             18  
             413  
             DNA  
             Papilloma virus  
           
            18 

ggatccactc cgttgtttgt gccctgtgca cgttgtaaaa aatatggcct attaaatatc     60 

tgagtttctg aagatgttaa agatccacta acagtattga aataaatatg tgaacctata    120 

ttttgctgag caccatcagt aggaggataa taatattcgc ctgctgtatt ttctggaata    180 

gtatctccca tttttcctcc ccgagcacca tgatgtctgg aatataactg ctctcgtaaa    240 

ccaaagaaaa atatatgatc tccataagga tctttattca tttttagaaa atcaggccac    300 

ttggaggtct catttataat gtctaaagga aatgaagctc tgtcctcgca tagattatca    360 

aaattcatag caccaaaacc tgtatcactc atctcaccgt cctccatgga tcc           413 

 
           
             19  
             428  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(426)  
             
           
            19 

gga tcc att caa gat ggg gat atg tgc gat att ggc ttt gga gca gcc       48 
Gly Ser Ile Gln Asp Gly Asp Met Cys Asp Ile Gly Phe Gly Ala Ala 
 1               5                   10                  15 

aat ttt aaa gca tta cag caa gat aaa tca ggt gtt cct tta gat att       96 
Asn Phe Lys Ala Leu Gln Gln Asp Lys Ser Gly Val Pro Leu Asp Ile 
             20                  25                  30 

gtt gac agt ata tgt aaa tgg cca gat att att aaa atg gag caa gaa      144 
Val Asp Ser Ile Cys Lys Trp Pro Asp Ile Ile Lys Met Glu Gln Glu 
         35                  40                  45 

ata tat gga gac aga tta ttt ttc ttt act aaa cgt gag caa gct tat      192 
Ile Tyr Gly Asp Arg Leu Phe Phe Phe Thr Lys Arg Glu Gln Ala Tyr 
     50                  55                  60 

gcc agg cat tat ttc gct cgt gca gga att aat ggt gat tct tta cca      240 
Ala Arg His Tyr Phe Ala Arg Ala Gly Ile Asn Gly Asp Ser Leu Pro 
 65                  70                  75                  80 

gat gca atg aaa cca gga gaa tat tat ctc tct cct aag ttg gga gat      288 
Asp Ala Met Lys Pro Gly Glu Tyr Tyr Leu Ser Pro Lys Leu Gly Asp 
                 85                  90                  95 

gag caa gta ccc cag aaa gac tta gga tcg cat att tat ttt cct aca      336 
Glu Gln Val Pro Gln Lys Asp Leu Gly Ser His Ile Tyr Phe Pro Thr 
            100                 105                 110 

gtt agt ggt tct ttg gtt tct agt gaa aat cag tta ttt aac aga cca      384 
Val Ser Gly Ser Leu Val Ser Ser Glu Asn Gln Leu Phe Asn Arg Pro 
        115                 120                 125 

tat tgg ttg cag aaa tct cag ggc aca aac aac ggc gtg gat              426 
Tyr Trp Leu Gln Lys Ser Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135                 140 

cc                                                                   428 

 
           
             20  
             142  
             PRT  
             Papilloma virus  
           
            20 

Gly Ser Ile Gln Asp Gly Asp Met Cys Asp Ile Gly Phe Gly Ala Ala 
 1               5                  10                  15 

Asn Phe Lys Ala Leu Gln Gln Asp Lys Ser Gly Val Pro Leu Asp Ile 
            20                  25                  30 

Val Asp Ser Ile Cys Lys Trp Pro Asp Ile Ile Lys Met Glu Gln Glu 
        35                  40                  45 

Ile Tyr Gly Asp Arg Leu Phe Phe Phe Thr Lys Arg Glu Gln Ala Tyr 
    50                  55                  60 

Ala Arg His Tyr Phe Ala Arg Ala Gly Ile Asn Gly Asp Ser Leu Pro 
65                  70                  75                  80 

Asp Ala Met Lys Pro Gly Glu Tyr Tyr Leu Ser Pro Lys Leu Gly Asp 
                85                  90                  95 

Glu Gln Val Pro Gln Lys Asp Leu Gly Ser His Ile Tyr Phe Pro Thr 
            100                 105                 110 

Val Ser Gly Ser Leu Val Ser Ser Glu Asn Gln Leu Phe Asn Arg Pro 
        115                 120                 125 

Tyr Trp Leu Gln Lys Ser Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135                 140 

 
           
             21  
             428  
             DNA  
             Papilloma virus  
           
            21 

ggatccacgc cgttgtttgt gccctgagat ttctgcaacc aatatggtct gttaaataac     60 

tgattttcac tagaaaccaa agaaccacta actgtaggaa aataaatatg cgatcctaag    120 

tctttctggg gtacttgctc atctcccaac ttaggagaga gataatattc tcctggtttc    180 

attgcatctg gtaaagaatc accattaatt cctgcacgag cgaaataatg cctggcataa    240 

gcttgctcac gtttagtaaa gaaaaataat ctgtctccat atatttcttg ctccatttta    300 

ataatatctg gccatttaca tatactgtca acaatatcta aaggaacacc tgatttatct    360 

tgctgtaatg ctttaaaatt ggctgctcca aagccaatat cgcacatatc cccatcttga    420 

atggatcc                                                             428 

 
           
             22  
             416  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(414)  
             
           
            22 

gga tcc ctg gaa gat ggt gaa atg gga gat att ggg ttt ggt gca gca       48 
Gly Ser Leu Glu Asp Gly Glu Met Gly Asp Ile Gly Phe Gly Ala Ala 
 1               5                   10                  15 

aat ttt aaa acg tta caa aag gac aga gcc gga gtc agc tta gat tta       96 
Asn Phe Lys Thr Leu Gln Lys Asp Arg Ala Gly Val Ser Leu Asp Leu 
             20                  25                  30 

gta gac act ttt agc att tgg cct gac ttt tta aaa atg act aat gat      144 
Val Asp Thr Phe Ser Ile Trp Pro Asp Phe Leu Lys Met Thr Asn Asp 
         35                  40                  45 

att tac gga gat agt atg ttt ttc ttt gga aaa cgt gag cag ctc ttt      192 
Ile Tyr Gly Asp Ser Met Phe Phe Phe Gly Lys Arg Glu Gln Leu Phe 
     50                  55                  60 

ggc aga cat ctt tgg aca aga gca ggt act ccc ggc gat gca att cct      240 
Gly Arg His Leu Trp Thr Arg Ala Gly Thr Pro Gly Asp Ala Ile Pro 
 65                  70                  75                  80 

act cca gaa aat ata aac tta ata ttt cca gct gat gat ggc act agt      288 
Thr Pro Glu Asn Ile Asn Leu Ile Phe Pro Ala Asp Asp Gly Thr Ser 
                 85                  90                  95 

caa aag gat gca ggg tct ttc act tac ttt act tca gct agt gga tct      336 
Gln Lys Asp Ala Gly Ser Phe Thr Tyr Phe Thr Ser Ala Ser Gly Ser 
            100                 105                 110 

ctt aat act agc gat tca caa tta ttt aat aga cct tac tgg ctt cga      384 
Leu Asn Thr Ser Asp Ser Gln Leu Phe Asn Arg Pro Tyr Trp Leu Arg 
        115                 120                 125 

cgt gca caa ggc aca aac aat ggc gtg gat cc                           416 
Arg Ala Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135 

 
           
             23  
             138  
             PRT  
             Papilloma virus  
           
            23 

Gly Ser Leu Glu Asp Gly Glu Met Gly Asp Ile Gly Phe Gly Ala Ala 
 1               5                  10                  15 

Asn Phe Lys Thr Leu Gln Lys Asp Arg Ala Gly Val Ser Leu Asp Leu 
            20                  25                  30 

Val Asp Thr Phe Ser Ile Trp Pro Asp Phe Leu Lys Met Thr Asn Asp 
        35                  40                  45 

Ile Tyr Gly Asp Ser Met Phe Phe Phe Gly Lys Arg Glu Gln Leu Phe 
    50                  55                  60 

Gly Arg His Leu Trp Thr Arg Ala Gly Thr Pro Gly Asp Ala Ile Pro 
65                  70                  75                  80 

Thr Pro Glu Asn Ile Asn Leu Ile Phe Pro Ala Asp Asp Gly Thr Ser 
                85                  90                  95 

Gln Lys Asp Ala Gly Ser Phe Thr Tyr Phe Thr Ser Ala Ser Gly Ser 
            100                 105                 110 

Leu Asn Thr Ser Asp Ser Gln Leu Phe Asn Arg Pro Tyr Trp Leu Arg 
        115                 120                 125 

Arg Ala Gln Gly Thr Asn Asn Gly Val Asp 
    130                 135 

 
           
             24  
             416  
             DNA  
             Papilloma virus  
           
            24 

ggatccacgc cattgtttgt gccttgtgca cgtcgaagcc agtaaggtct attaaataat     60 

tgtgaatcgc tagtattaag agatccacta gctgaagtaa agtaagtgaa agaccctgca    120 

tccttttgac tagtgccatc atcagctgga aatattaagt ttatattttc tggagtagga    180 

attgcatcgc cgggagtacc tgctcttgtc caaagatgtc tgccaaagag ctgctcacgt    240 

tttccaaaga aaaacatact atctccgtaa atatcattag tcatttttaa aaagtcaggc    300 

caaatgctaa aagtgtctac taaatctaag ctgactccgg ctctgtcctt ttgtaacgtt    360 

ttaaaatttg ctgcaccaaa cccaatatct cccatttcac catcttccag ggatcc        416 

 
           
             25  
             425  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(423)  
             
           
            25 

gga tcc cta gag gat ggg gag atg ggt gat ata gga ttt ggt gct gct       48 
Gly Ser Leu Glu Asp Gly Glu Met Gly Asp Ile Gly Phe Gly Ala Ala 
 1               5                   10                  15 

aat ttt gct aag ctt atg caa gat aga gct ggt gta cct ctg gaa tta       96 
Asn Phe Ala Lys Leu Met Gln Asp Arg Ala Gly Val Pro Leu Glu Leu 
             20                  25                  30 

ata gat agt att agt ata tgg cca gat ttt cta aaa atg aca aag gat      144 
Ile Asp Ser Ile Ser Ile Trp Pro Asp Phe Leu Lys Met Thr Lys Asp 
         35                  40                  45 

att tat gga aat gaa gta ttt ttc ttt gga aaa cgc gag caa tgt tat      192 
Ile Tyr Gly Asn Glu Val Phe Phe Phe Gly Lys Arg Glu Gln Cys Tyr 
     50                  55                  60 

gct cgc cat tta ttt gcc aga gct ggt act atg gga gaa cca gta cct      240 
Ala Arg His Leu Phe Ala Arg Ala Gly Thr Met Gly Glu Pro Val Pro 
 65                  70                  75                  80 

aat gag act aat gga gta aat ttt ata aat gca aaa cca gga gat cca      288 
Asn Glu Thr Asn Gly Val Asn Phe Ile Asn Ala Lys Pro Gly Asp Pro 
                 85                  90                  95 

aat ccc agg agc gct cat atg ggt tct tca gta tac ttt gca aca cct      336 
Asn Pro Arg Ser Ala His Met Gly Ser Ser Val Tyr Phe Ala Thr Pro 
            100                 105                 110 

agt ggc tcc ctt aat acc agt gat tca caa ata ttt aac aga cct tat      384 
Ser Gly Ser Leu Asn Thr Ser Asp Ser Gln Ile Phe Asn Arg Pro Tyr 
        115                 120                 125 

tgg tta cga cgg gct caa gga acg aac aac ggc atg gat cc               425 
Trp Leu Arg Arg Ala Gln Gly Thr Asn Asn Gly Met Asp 
    130                 135                 140 

 
           
             26  
             141  
             PRT  
             Papilloma virus  
           
            26 

Gly Ser Leu Glu Asp Gly Glu Met Gly Asp Ile Gly Phe Gly Ala Ala 
 1               5                  10                  15 

Asn Phe Ala Lys Leu Met Gln Asp Arg Ala Gly Val Pro Leu Glu Leu 
            20                  25                  30 

Ile Asp Ser Ile Ser Ile Trp Pro Asp Phe Leu Lys Met Thr Lys Asp 
        35                  40                  45 

Ile Tyr Gly Asn Glu Val Phe Phe Phe Gly Lys Arg Glu Gln Cys Tyr 
    50                  55                  60 

Ala Arg His Leu Phe Ala Arg Ala Gly Thr Met Gly Glu Pro Val Pro 
65                  70                  75                  80 

Asn Glu Thr Asn Gly Val Asn Phe Ile Asn Ala Lys Pro Gly Asp Pro 
                85                  90                  95 

Asn Pro Arg Ser Ala His Met Gly Ser Ser Val Tyr Phe Ala Thr Pro 
            100                 105                 110 

Ser Gly Ser Leu Asn Thr Ser Asp Ser Gln Ile Phe Asn Arg Pro Tyr 
        115                 120                 125 

Trp Leu Arg Arg Ala Gln Gly Thr Asn Asn Gly Met Asp 
    130                 135                 140 

 
           
             27  
             425  
             DNA  
             Papilloma virus  
           
            27 

ggatccatgc cgttgttcgt tccttgagcc cgtcgtaacc aataaggtct gttaaatatt     60 

tgtgaatcac tggtattaag ggagccacta ggtgttgcaa agtatactga agaacccata    120 

tgagcgctcc tgggatttgg atctcctggt tttgcattta taaaatttac tccattagtc    180 

tcattaggta ctggttctcc catagtacca gctctggcaa ataaatggcg agcataacat    240 

tgctcgcgtt ttccaaagaa aaatacttca tttccataaa tatcctttgt catttttaga    300 

aaatctggcc atatactaat actatctatt aattccagag gtacaccagc tctatcttgc    360 

ataagcttag caaaattagc agcaccaaat cctatatcac ccatctcccc atcctctagg    420 

gatcc                                                                425 

 
           
             28  
             398  
             DNA  
             Papilloma virus  
             
               CDS  
               (1)...(396)  
             
           
            28 

gga tcc ctt gag gat ggg gaa atg ata gat aca ggc tat ggt gcc atg       48 
Gly Ser Leu Glu Asp Gly Glu Met Ile Asp Thr Gly Tyr Gly Ala Met 
 1               5                   10                  15 

gac ttt cgt aca ttg cag gaa acc aaa agt gag gta cca cta gat att       96 
Asp Phe Arg Thr Leu Gln Glu Thr Lys Ser Glu Val Pro Leu Asp Ile 
             20                  25                  30 

tgc caa tcc gtg tgt aaa tat cct gat tat ttg cag atg tct gct gat      144 
Cys Gln Ser Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp 
         35                  40                  45 

gta tat ggg gac agt atg ttt ttt tgt ttg cgc aag gaa cag ttg ttt      192 
Val Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Lys Glu Gln Leu Phe 
     50                  55                  60 

gcc agg cac ttt tgg aat aga ggt ggc atg gtg ggc gac aca ata cct      240 
Ala Arg His Phe Trp Asn Arg Gly Gly Met Val Gly Asp Thr Ile Pro 
 65                  70                  75                  80 

tca gag tta tat att aaa ggc acg gat ata cgt gag cgt cct ggt act      288 
Ser Glu Leu Tyr Ile Lys Gly Thr Asp Ile Arg Glu Arg Pro Gly Thr 
                 85                  90                  95 

cat gta tat tcc cct tcc cca agt ggc tct atg gtc tct tct gat tcc      336 
His Val Tyr Ser Pro Ser Pro Ser Gly Ser Met Val Ser Ser Asp Ser 
            100                 105                 110 

cag ttg ttt aat aag ccc tat tgg ttg cat aag gcc caa ggc cac aat      384 
Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn 
        115                 120                 125 

aac ggg atg gat cc                                                   398 
Asn Gly Met Asp 
    130 

 
           
             29  
             132  
             PRT  
             Papilloma virus  
           
            29 

Gly Ser Leu Glu Asp Gly Glu Met Ile Asp Thr Gly Tyr Gly Ala Met 
 1               5                  10                  15 

Asp Phe Arg Thr Leu Gln Glu Thr Lys Ser Glu Val Pro Leu Asp Ile 
            20                  25                  30 

Cys Gln Ser Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp 
        35                  40                  45 

Val Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Lys Glu Gln Leu Phe 
    50                  55                  60 

Ala Arg His Phe Trp Asn Arg Gly Gly Met Val Gly Asp Thr Ile Pro 
65                  70                  75                  80 

Ser Glu Leu Tyr Ile Lys Gly Thr Asp Ile Arg Glu Arg Pro Gly Thr 
                85                  90                  95 

His Val Tyr Ser Pro Ser Pro Ser Gly Ser Met Val Ser Ser Asp Ser 
            100                 105                 110 

Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn 
        115                 120                 125 

Asn Gly Met Asp 
    130 

 
           
             30  
             398  
             DNA  
             Papilloma virus  
           
            30 

ggatccatcc cgttattgtg gccttgggcc ttatgcaacc aatagggctt attaaacaac     60 

tgggaatcag aagagaccat agagccactt ggggaagggg aatatacatg agtaccagga    120 

cgctcacgta tatccgtgcc tttaatatat aactctgaag gtattgtgtc gcccaccatg    180 

ccacctctat tccaaaagtg cctggcaaac aactgttcct tgcgcaaaca aaaaaacata    240 

ctgtccccat atacatcagc agacatctgc aaataatcag gatatttaca cacggattgg    300 

caaatatcta gtggtacctc acttttggtt tcctgcaatg tacgaaagtc catggcacca    360 

tagcctgtat ctatcatttc cccatcctca agggatcc                            398