The present invention relates to gene and peptide sequences of a diabetes-specific endogenous retrovirus which is derived from type 1 diabetes patients. In particular, the present invention relates to a whole genome of the diabetes-specific variant of endogenous retrovirus (ERV-9) purified from pancreatic tissues of type 1 diabetes (insulin-dependent diabetes mellitus IDDM) patients and its genes and peptide and their sequences, which can be used as a diagnosing reagent for type 1 diabetes and as an immunogen.The diabetes-specific retrovirus expressed exclusively in pancreatic beta cells was purified from deceased type 1 diabetes patients. Subsequently, the retroviral gene sequences were determined, and by analyzing the amino acid sequence of the peptide deduced from the gene, 21 domains of the peptide having hydrophilicity and immuno-dominancy were identified.Therefore, the variant gene of the endogenous retrovirus and the peptide deduced from the gene can be effectively used as a diagnosing reagent of autoimmune-antibody for type 1 diabetes and as a vaccine for the variant ERV-9 related diseases.

Description

34 parts

›FIELD OF THE INVENTION

The present invention relates to the gene and peptide sequences of a diabetes-specific endogenous retrovirus derived from type 1 diabetes patients. In particular, the present invention relates to the whole genome of the diabetes-specific variant of endogenous retrovirus (ERV-9) purified from pancreatic tissues of type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]) patients, and viral genes and peptides sequences which can be used to develop a diagnosing reagent for type 1 diabetes and an immunogen.

›BACKGROUND OF THE INVENTION

It is known that the human genome contains a complex variety of inherited endogenous retroviral sequences, several of which are transcriptionally active and contain open reading frames. Aberrant expression of endogenous retroviral sequences has been implicated in the pathogenesis of many autoimmune diseases, including Sjogren's syndrome (Hao W., et al., J. Autoimmune , 6: 787-798, 1993), rheumatoid arthritis (Garry R. F., Arthritis and Rheumatism , 37: 465-469, 1994), systemic lupus erythematosus (Wilder R. L., Current Opinions in Rheumatology , 6: 295-299, 1994), Hashimoto's thyroiditis (Blomberg J., et al., Arthritis and Rheumatism . 37: 57-66, 1994), Graves' disease (Blomberg J., et al., Arthritis and Rheumatism . 37: 57-66, 1994) and the like. In addition, some infectious exogenous retroviruses cause manifestations of autoimmunity (Tomer Y., et al., Endocrine Reviews , 14: 107-120, 1993).

Type 1 diabetes, also known as insulin-dependent diabetes mellitus, is an autoimmune diseases resulting from the destruction of pancreatic beta cells by beta cell-specific autoimmune processes. However, the processes which trigger the autoimmunity remain unknown. In the pancreatic beta cells of non-obese diabetic (NOD) mice, a spontaneously diabetic animal model for human type 1 diabetes, the presence of retrovirus particles in pancreatic beta cells, which is known to be associated with insulitis and diabetes, has been reported. The initiation of insulitis in NOD mice is known to occur at 4 to 6 weeks of age. Fujita et al. observed retrovirus particles in NOD mice as young as 2 days old using electron microscopy (Fujita H., et al., Biochemical Research , 5(1): 71-76, 1984). In addition, Serreze et al. found that anti-type C retrovirus antibody shows peak titer shortly after weaning in NOD mice (Serreze D. V., et al., Diabetes , 37: 351-358, 1988). In this study, type C retrovirus particles were found in both intact and lymphocyte-infiltrated islets, and retrovirus particles were also detected in beta cells showing severe nuclear damage within intact islets which showed no evidence of lymphocytic infiltration. In another study, Like and Rossini observed the induction of aberrant retrovirus budding into the rough endoplasmic reticulum of the beta cells, two to three days before insulitis developed in male CD-1 mice treated with multiple doses of streptozotocin (Like A. A. and Rossini A. A., Science , 193: 415-417, 1976). These results suggest that the expression of retrovirus occurs prior to lymphocytic infiltration of the islets. Thus, the expression of retrovirus has been assumed to be an initial event in the damage of beta cells, rather than the result of insulitis.

To date, there has been no report of the exclusive expression of retrovirus particles in the beta cells of recent-onset type 1 diabetes patients. Thus, an examination on whether retrovirus particles are expressed in pancreatic tissues of type 1 diabetes patients was required to clarify the etiology of the onset of autoimmune type 1 diabetes.

Therefore, the present inventors have extensively examined the expression of retrovirus particles in pancreatic tissues of type 1 diabetes patients, and have found that retrovirus particles are expressed specifically in the pancreatic beta cells of diabetes patients. This fact can be exploited to develop a diagnosing reagent for type 1 diabetes and an immunogen. In particular 21 domains deduced from the above retroviral gene were elucidated to develop new peptides for vaccines and the like because these domains show hydrophilicity and immuno-dominancy.

The present inventors have also elucidated that the diabetes-specific retrovirus is an endogenous retrovirus (ERV-9) variant.

Although a direct relationship between the onset of type 1 diabetes and the expression of diabetes-specific endogenous retrovirus (ERV-9) was found, the role of beta cell-specific expression of retroviruses in the pathogenesis of beta cell-specific autoimmunity remains unknown. There are three possible mechanisms whereby retrovirus may be involved in the etiology of the disease.

First, the presentation of a retroviral antigen of the beta cells by MHC class II molecules from antigen-presenting cells (APCs) , such as macrophages, may be the initial step in the autoimmune destruction of beta cells (Chomczynski P., et al., Anal. Biochem ., 162: 156, 1987; Froussard P. A., Nucleic Acids Research , 20(11): 2900, 1992; Shin A., et al., J. virol ., 63(1): 64-75, 1989). An immune response to a specific antigen on a target cell involves the activation of CD4 + T cells, which are activated only when they interact with antigens presented on the surface of a macrophage or other APC.

Second, retroviral genome in the beta cells may alter the expression of cellular genes, possibly resulting in a beta cell-specific altered antigen(s) which could be recognized as foreign by the immune system. The retroviral antigen or altered beta cell antigen might be presented by MHC class I molecules and recognized as foreign by CD8 + cytotoxic T cells (CTLs). Subsequently, signals transduced through T cell receptors (TcR) may be activated and CTLs may produce cytokines such as interferon-γ(INF-γ) which would, in turn, induce inflammation and further stimulate antigen presentation, leading to beta cell-specific autoimmunity (York I. A. and Rock K. L., Annu. Rev. Immunol ., 14: 369-396, 1996).

Third, retroviral antigen-specific effector T cells, which may recognize autoantigens expressed on the beta cells by molecular mimicry, may be generated.

›SUMMARY OF THE INVENTION

The object of the present invention is to provide a whole genome of a diabetes-specific endogenous retrovirus (ERV-9) derived from the pancreatic tissues of type 1 diabetes patients, including the gag gene, pol gene, and env gene of the viral genome and their nucleotide sequences, shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:4 and SEQ ID NO:6, respectively.

The object of the present invention is to provide amino acid sequences deduced from the above gene sequences. In particular, the Gag protein has the amino acid sequence shown in SEQ ID NO:3, the Pol protein has the amino acid sequence shown in SEQ ID NO:5 and the Env gene has the amino acid sequence shown in SEQ ID NO:7.

The object of the present invention is to provide antigens of the diabetes-specific endogenous retrovirus (ERV-9) containing the entire or partial amino acid sequence deduced from the above gag, pol or env gene sequences.

The object of the present invention is to provide antibodies for the diabetes-specific endogenous retrovirus (ERV-9), prepared by using the above antigens.

The object of the present invention is to provide vaccines for the diabetes-specific endogenous retrovirus (ERV-9) containing the above antigens as effective agents.

The object of the present invention is to provide diagnosing reagents for diabetes, which are prepared by using the above nucleotide sequences entirely and partially.

The object of the present invention is to provide diagnosing reagents for diabetes, which are prepared by using the entire or partial peptide sequences derived from Gag, Pol or Env protein.

The object of the present invention is to provide diagnosing reagents for diabetes, which are prepared by exploiting the above antibodies.

The object of the present invention is to provide a peptide and its derivative, which comprises the amino acid sequence containing the antigenic determinant or immuno-dominant domain deduced from the gene sequence of the diabetes-specific endogenous retrovirus (ERV-9).

The object of the present invention is to provide diagnosing reagents for diabetes, which contain the above peptide as an effective agent.

The object of the present invention is to provide antibodies for the diabetes-specific endogenous retrovirus (ERV-9), which are prepared by using the above peptide.

The object of the present invention is to provide vaccines for diseases related to the diabetes-specific endogenous retrovirus (ERV-9), which contain the above peptide as an effective agent.

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the hydrophilicity/hydrophobicity of the peptide deduced from the gag gene sequence of a diabetes-specific endogenous retrovirus (ERV-9).

FIG. 2 is a graph showing the hydrophilicity/hydrophobicity of the peptide deduced from the pol gene sequence of a diabetes-specific endogenous retrovirus (ERV-9).

FIG. 3 is a graph showing the hydrophilicity/hydrophobicity of the peptide deduced from the env gene sequence of a diabetes-specific endogenous retrovirus (ERV-9).

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 2

The present invention provides the genome of a diabetes-specific retrovirus, which is a variant of human endogenous retrovirus (ERV-9).

The diabetes-specific retrovirus of the present invention was purified from the pancreatic tissues of deceased type 1 diabetes patients and was identified to be expressed exclusively in pancreatic beta cells of the above patients. The nucleotide sequence of the gene is shown in SEQ ID NO:1.

The present invention provides diabetes-specific retroviral genes and their nucleotide sequences, which clarify that the retrovirus is a variant of a known human endogenous retrovirus (ERV-9). The nucleotide sequences of the gag gene, pol gene and env gene of the viral gene are shown in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, respectively, wherein * is a termination codon.

In addition, the present invention provides amino acid sequences deduced from the above genes, by which 21 domains showing hydrophilicity and immuno-dominancy were identified. The Gag protein has the amino acid sequence shown in SEQ ID NO:3, the Pol protein has the amino acid sequence shown in SEQ ID NO:5, and the Env gene has the amino acid sequence shown in SEQ ID NO:7.

In detail, pancreata were obtained from four deceased, recent-onset type 1 diabetes patients and were embedded in paraffin. The embedded pancreata were sliced into sections and stained with hematoxylin-eosin (HE). In the sections, severe necrosis of the pancreatic islets with lymphocytic infiltration was observed, and lymphocytic destruction of the beta cells in the four patients was detected in all the pieces of each pancreas tail using electron microscopy. In addition, using the immunofluorescence method, the infiltrating lymphocytes were identified as CD8 + T cells, CD4 + T cells, macrophages and natural killer cells. The above retroviruses in the cytoplasm of the beta cells of the four diabetes patients were identified as C-type retrovirus particles, which are enveloped and spherical, with a diameter of about 120 nm and a dense central nucleoid. In contrast, other islet endocrine cells, such as alpha, delta and polypeptide-producing cells, as well as exocrine acinar cells, were intact and did not contain retrovirus particles. Retrovirus particles were not found in brain cells and spleen cells from the diabetes patients or normal controls.

Although the beta cell-specific expression of retrovirus particles was identified by electron microscopy, the sequences of the above retroviral gene found in the above diabetes patients and normal controls were determined because retrovirus particles could be present without detection in other tissues considering the limitations-of sectioning. As a result, a number of retroviral sequences were found to be present in both diabetes patients and normal controls. These common sequences were excluded from the type 1 diabetes-specific retrovirus. However, only one retroviral gene (particularly at the RNA level) was found in the pancreata from the four diabetes patients and not detected in the pancreata from normal controls. This viral gene sequence has homology with a human endogenous retroviral sequence (ERV-9; NIH GenBank Accession #85205).

In order to clone the whole genome of the diabetes-specific retrovirus, various primers were designed. First, using one primer from the above diabetes-specific sequence and another primer from the ERV-9 sequence, DNA fragments of 400 to 500 base pairs were amplified from a cDNA library of the pancreata of diabetes patients and cloned into a cloning vector, and the nucleotide sequences of the fragments were determined. Considering the sequence information, another primer was designed from the known sequence and the above processes were repeated in order to elucidate the whole gene sequences. As a result, it is known that the total number of nucleotides is 3910 and that this variant viral gene of the present invention has approximately 80% homology with a known human endogenous retrovirus (ERV-9) gene.

Comparing the diabetes-specific viral gene of the present invention with other retroviral gene, the structure of the gag, pol and env genes were determined, and amino acid sequences of the proteins were deduced from the above gene sequences. The antigenic determinant or immuno-dominant domain was detected and the hydrophilicity /hydrophobicity of the Gag, Pol and Env proteins were examined by analyzing the amino acid sequences. In particular, 21 domains of the viral proteins, having the amino acid sequences shown in SEQ ID NO: 8 to SEQ ID NO: 28 and their functional equivalents are identified to have hydrophilicity and immuno-dominancy. In the above SEQ ID NO: 8 to SEQ ID NO: 28, X can correspond to any amino acid available. In the above peptides, cysteine or an additional amino acid sequence such as Gly-Gly, Ser-Gly-Ser-Gly or the like can be added onto the N-terminus of the peptide. Amide (—NH 2 ) , acetate (—COOH) or the like can be added onto the C-terminus of the peptide. The functional equivalents of the peptide can be selected from among analogue, complex, fragment, polymer, conjugate and mixture of the peptide having 21 domains. The above conjugate is a carrier protein conjugated peptide which is prepared by conjugating carrier protein onto the peptide with a disulfide bond, wherein the peptide has more than one of the 21 domains of peptide or the peptide by which an additional amino acid sequence such as Gly-Gly, Ser-Gly-Ser-Gly or the like is attached onto the N-terminus of the 21 domain peptide. The conjugate is also a biotin conjugated peptide which is prepared by conjugating biotin onto the 21 domain peptide by which an additional amino acid sequence such as Gly-Gly or Ser-Gly-Ser-Gly can be attached onto the N-terminus. The polymer is a branched form polymerized using poly-L-lysine resin such as Lys 8 Lys 4 Lys 2 Lys-Y (wherein Y is amino acid or cysteine without —OH, —NH 2 , branched functional group).

The present invention provides antigens of the diabetes-specific endogenous retrovirus (ERV-9) and antibodies for the antigen which can be prepared by using the peptide or the viral proteins derived from the above gene.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 2

The present invention provides diagnosing reagents for diabetes or vaccines for diabetes which can be prepared by using the antigens and antibodies of the present invention. In addition, the above 21 domain peptides and their functional equivalents are previded, which can be synthesized by using the above sequences and the like and also can be exploited for diagnosing reagents for diabetes or vaccines for diabetes.

The present invention is further illustrated with reference to the following examples which are not intended to be in any way limiting to the scope of the invention as claimed.

›Examples6

›EXAMPLE 1

Receipt of the pancreatic tissue samples

The present inventors received pancreata from four deceased, recent-onset type 1 diabetes patients. The first patient was a one year old girl, who died within one week of diagnosis of diabetes. There was no family history of autoimmune or endocrine diseases. The girl's blood glucose level was 406 mg/dl and her HLA type was DR3/14, DQ1/2. The second patient was a three year old girl, who lacked diabetes symptoms until she developed post-operative complications and severe hyperglycemia (a blood glucose level of 880 mg/dl). This patient's HLA type was DR1/7. The third and fourth patients were eight and ten year old boys, who both died of brain swelling during treatment for diabetes ketoacidosis shortly after diagnosis of type 1 diabetes. The ten non-diabetes control pancreata were obtained from the University of Calgary and the University of Alberta.

›EXAMPLE 2

Observation of the pancreatic tissue samples

Examination of paraffin-embedded, hematoxylin-eosin (HE) stained sections of the pancreata from the four type 1 diabetes patients revealed severe necrosis of the pancreatic islets with lymphocytic infiltration. As a result of observation on the acetone-fixed frozen pancreatic tissues by the direct or indirect immuno-fluorescence method, using staining with monoclonal antibodies for leu M1 antigen and CD15 antigen for macrophages; leu2a antigen for CD4 + T cells; leu 3a antigen for CD8 + T cells; and leu 7 antigen and CD57 antigen for natural killer(NK) cells, the infiltrating immunocytes were determined to be CD8 + T cells, CD4 + T cells, macrophages and NK cells. Herein, CD4 + T cells were slightly observed in patient 1 and both CD8 + T cells and CD4 + T cells were observed in patients 3 and 4. All four patients were found to be negative by indirect immunofluorescence using polyclonal antibody for rubella, CMV, Cox B4 virus and Parvo virus B19.

In part, lymphocytic destruction of beta cells in all four patients was revealed by the examination on an acetone-fixed ultra-thin piece of the tail of each pancreas by electron microscopy. That is, in patient 2, the nuclei of the beta cells were swollen and the chromatin was aggregated, and in other patients, the chromatin of the normal pancreatic duct cell was dense or pale. In addition, C-type retrovirus particles were found in the cytoplasm of intact or lymphocyte-infiltrated pancreatic beta cells of the four diabetes patients. The retrovirus was enveloped and spherical, with a diameter of about 120 nm and a dense central nucleoid. In contrast, other islet endocrine cells, which are alpha, delta and polypeptide-producing cells, as well as exocrine acinar cells, were intact and did not contain retrovirus particles. In addition, brain and spleen cells from diabetes patients or non-diabetic control subjects did not contain retrovirus particles.

›EXAMPLE 3

RNA extraction from pancreatic tissue and synthesis of CDNA

The total RNA was extracted from frozen pancreatic tissue of the type 1 diabetes patients and healthy controls using the acid guanidium isothiocyanate-phenol chloroform extraction method, and the first cDNA strand was synthesized by the following method. The extracted RNA was dissolved in 4.4 μl of distilled water, to which 0.6 μl (20 units) of RNAsin, 4.3 μl of 5-fold concentrated Superscript buffer solution, 2 μl of mixed dNTPs (10 mM), 1 μl (200 ng) of Universal primer-dN6 (5′-GCCGGAGCTCTGCAGAA TTCNNNNNN-3′) and 2.2 μl of DTT (50 mM) were added, heated at 65° C. for 5 minutes and immediately cooled in an ice bath. Secondly, 1.6 μl (16 units) of Superscript reverse transcriptase (Gibco BRL. Gaithersberg, Md., USA) was added and reacted at 37° C. for 1 hour. Then, the reaction-terminated mixture was centrifuged at 4° C., boiled at 100° C. for 2 minutes and immediately cooled in an ice bath.

Subsequently, the second cDNA strand was synthesized by the following method. To the above reaction-terminated mixture, 15 μl of distilled water, 10 μl of 5-fold concentrated Klenow buffer solution, 1 μl of dCTP and 1.5 μl (9 units) of Klenow enzyme were added, centrifuged momentarily at 4° C. and maintained at 37° C. for reaction. The excess Universal primer-dN6 was cleared off by the process in which, after 200 μl of distilled water was added to the above reaction-terminated mixture, the mixture was passed through a Cetri-Sep™ spin column (Princeton Separations, Inc., Adelphia, N.J., U.S.A.) and centrifuged at 4000 rpm for 5 minutes.

PCR was performed by the following process in order to amplify the double-helical cDNA synthesized at random: 10 μl of 10-fold concentrated PCR buffer solution (Perkin Elmer, U.S.A.), 6 μl of 25 mM magnesium chloride solution, 500 μM of each dNTP, 1 μl of Universal primer (200 ng) and 0.5 μl (2.5 units) of Taq DNA synthesis enzyme (Gibco BRL, Gaithersberg, Md., U.S.A.) were added to the above cDNA solution to adjust the final reaction volume to 100 μl. An equal volume of mineral oil was layered on the surface of the reactant solution and the cDNA was amplified for 35 cycles at 94° C. for 1 min, 55° C. for 1 min and 72° C. for 2 min using a TR-96 model heating incubator.

›EXAMPLE 4

Cloning of the retrovirus gene

The reverse transcriptase gene fragment from the cDNA library of <Example 3> was amplified using a mixed oligonucleotide primer (MOP) of the following sequence derived from the conserved region of the reverse transcriptase gene:

5′-TGGAAAGTG(T,C)T(G,A)CC(A,C)CA(A,G)GG-3′

3′-ATG(T,C)ACCTACTG(T,G)A(G,C)GACGACCGG(A,C)GG-5′

After the amplified gene was electrophoresed on an agarose gel followed by staining with ethidium bromide, the band with a length of 138 base pairs was cut and the gene fragment was extracted from the gel by the electro-extraction method. 6 μl of distilled water, 1 μl of 10-fold concentrated ligase buffer solution, 1 μl of T4 ligase and 2 μl (50 ng) of pCRII™ vector (TA cloning kit, Invitrogen, Carlsbad, Calif., U.S.A.) were added to 1 μl of the extracted reverse transcriptase gene and reacted at 12° C. for 12 hours (overnight). Subsequently, 1 μl of the above ligation reaction mixture was mixed with INVaF′ strain and cooled in an ice bath for 30 min in order to transform the INVaF′ strain with a pCRII™ vector cloned with a reverse transcriptase gene. Subsequently, the mixture was reacted in a 45° C. water bath for exactly 45 seconds and cooled in an ice bath for 2 min. Next, 450 μl of SOC media was added to each reaction tube and the tubes were incubated at 37° C. for 1 hour. Next, 100 μl of transformed cell suspension was layered on LB agarose plates containing 50 μl of ampicillin (50 μg/ml) and 50 μl of X-Gal (20 mg/ml) and the plates were incubated at 37° C.

›EXAMPLE 5

Sequencing of the retroviral gene

308 colonies containing viral gene fragments of 138 base pairs were obtained from <Example 4> and sequenced using a sequenase 2.0 kit (US Biochemicals) and a Taq Dideoxy™ terminator cycling sequence kit (Perkin Elmer, Foster City, Calif., U.S.A.) with 373A sequence analyzer (Applied Biosystem). The homology between the above analyzed sequence and the known nucleotide sequence was examined through the GenBank Data Base (NIH, USA), and it was found that the diabetes-specific nucleotide sequences from the four diabetes patients have approximately 85% homology with a known endogenous retrovirus gene (GenBank accession number #85205).

Next, by the following process, sequencing of the entire retrovirus gene was completed. One primer from the diabetes-specific sequence and one primer from the ERV-9 sequence were designed to amplify a 400 to 500 base pair fragment. After amplification of the diabetes patients' cDNA library with these two primers, the fragments were cloned into a PCRII™ vector (Invitrogen, U.S.A.) and sequenced. By considering the sequence information, a primer was designed from the known sequence and the above processes were repeated in order to elucidate the whole gene sequences.

As a result, the total number of nucleotides was found to be 3910 and this variant viral gene was shown to have approximately 80% homology with a known human endogenous retrovirus (ERV-9) gene (SEQ ID NO:1). In addition, by comparing the diabetes-specific variant viral gene of ERV-9 with another retroviral gene, the site and the structure of the gag, pol and env genes were determined. The gag gene corresponds to nucleotides 1 to 396 of the variant viral gene, the pol gene corresponds to nucleotides 397 to 2726 and the env gene corresponds to nucleotides 2858 to 3322.

›EXAMPLE 6

Sequencing of the amino acids

The present inventors deduced the amino acid sequence of the protein produced according to the induced gene structure (SEQ ID NO: 3, 5, 7. Herein, * is deduced from termination codon). Therefore, the antigenic determinant domain or immunodominant domain was examined by analyzing amino acid sequences and the hydrophilicity/hydrophobicity was examined from each amino acid sequences of the gag (SEQ ID NO: 3), pol (SEQ ID NO: 5) and env (SEQ ID NO: 7) genes shown in FIG. 1, FIG. 2 and FIG. 3 .

As a result, the following 21 domains were expected to have hydrophilicity and immuno-dominancy (SEQ ID NO: 8 to SEQ ID NO: 28).

In the above SEQ ID NO: 8 to SEQ ID NO: 28, X can correspond to any amino acid.

›EFFECT OF THE INVENTION

As distinctly described above, the present invention provides the nucleotide sequences of the endogenous retrovirus variant (ERV-9) gene purified from pancreatic tissues of type 1 diabetes patients in which the viral gene is expressed specifically and also provides the amino acid sequences derived from the above viral genes. By analyzing the above sequences, 21 domains of the viral proteins are identified to have hydrophilicity and immuno-dominancy. Therefore, the peptide and its derivatives containing the above domains and the viral protein prepared by using the variant viral genes of the present invention can be utilized to develop antigens for the diabetes-specific virus. The above antigens can be used for diagnosing autoimmune antibodies of type 1 diabetes. In addition, vaccines for the variant ERV-9-related diseases can be developed by exploiting the above protein and peptides effectively.

3910

›DNA

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

cggagaaagc tccaaaagca agccctgggc cctgaacaaa atctggaggc attattaaac 60

ctggcaacct tagtgttcta taatagggtc cgagaggaac aggcccaaaa ggaaaagtga 120

gatcagagag aggccacagc cttagtcatg gccctcagac aaacaaacct tggtggttca 180

gagaggacag aaaatggatc aggccaatca cctggtaggg cttgttatca gtgtggttta 240

caaggacact ttaaaaaaga ttgtccaaca agaaacaagc caccccctca tccatgtccg 300

ctatgccgag ccaatcactg gaaggcacac tgccccagag tgaaatggtt ctctggccca 360

gaagccctca accagatgat ccaacaacag gactgagagt gcctgggcca agtgccagct 420

catgtcatca accttactga gtcccgggta tgtttaacca ttgagggcca ggaaattgac 480

ttcctcctgg acactggcat ggccttctca gtgttaatct cctgtcctgg atgactgtcc 540

tcaaggtcca ttaccatcca aggaatccta agacagccta taaccaggta tttctcccac 600

ctcctcagtt gtaattggga gactttgctc ttttcacatg cctttcttgt tatacctgaa 660

agtcccacac ccttattagg gagggatata ttagccaaag ctggagctat tacctatatg 720

aataagagga acaagttaac catttgttgt cctctacttg aggagggaat caaccctgaa 780

gtctgggcat tggaaggaca atttggaagg gcaaaaaatg cctgcccagt ccaaatcagg 840

ctaaaagacc ccaccacttt tcctatcaaa ggcaatatcc cttaaggcct gaagctcata 900

aaggattaca ggatattgct gaacatttaa tagctcaagg cttagtaagg aaatgcagca 960

gtccctgaaa cacgccaatt ctaggagtac aaaaaccgaa cggtcagtgg agactagtgc 1020

aagatcttag actcactaat gacgcagtaa ttcctctata tccagttgta cccaacccct 1080

ataccctgct ctctcaaata ccagaggaag cagaatggtt cacagttctg gacttcaagg 1140

atgccttctt ctgtgttccc ctgcactctg attcacagct cctctttgct tttgaggatc 1200

ccacaaacca cacatcccaa cttacatgga tggtcttgcc ccaagggttt agggatagcc 1260

ctcatctgtt tggtcaggcc ctagccaaag atctaagcca cttctcaggt ccaggcactc 1320

tggtccttca atatgtggat gatttacttt tggctaccag ttaggaagcc ttgtgccagc 1380

aggctactct agatctcttg aaccttctag ctaatcaagg gtacaaggtg tctatgttca 1440

aagcccaact ttgcctacag caggttaaat atctaggcct aatcttagcc aaagggacaa 1500

gggccctcag caaggaatga atacagccta tactggctta tcctcgccct aagacattaa 1560

aacagttgag ggagttcctt ggaattacca gcttttgccg actatggatc cctggataca 1620

gcgagacagc caggcccctc taatcaagga aacccagagg gcaaatactc atctagttga 1680

gtgggaacca gaggcagaaa caaccttcag aaccttaaag caggctctag tacaagctcc 1740

agctttaagc tttcccacag gacagaattt ctctttatat gtcagagaga gagccaggat 1800

agctattaga gtcctcactc aaactcatcg gactgcccca cgaccagtgg caaacctaag 1860

taaggaaatt gatgtagtag caaaaggctg gcctcagtgt ttaggggtag ttgcagctgt 1920

ggccgcctta gcatcagagg ctatcaaaat aatacaagga aaggatctca cagtctagac 1980

tacttatgat gttaatggca tactaggtgc ccaaggaagt ttatggctat cagataactg 2040

cctacttaga taccaggcac tactccttga gggaacagta cttaaaaaat gcacatgcat 2100

ggcccttaac cctgccactt ttctcacaga ggatcgggaa cctatcaagc aggactgaca 2160

acaaattata gtccagactt atgccgcccg agatgatctc ttaaaagtcc ccttaactaa 2220

tccagacctt aacctatata ctgatggaag ttcacttgtg gaccatgcga tacgtaggtt 2280

agttatgtaa cgatacttga aaacaagcct cttccgccag ggaccagtgc ccagttagcg 2340

gaactagtgg cacttacctt ggcctcagaa gtgggatggg caaaagaata aatttgttta 2400

gagatagcag gtatgcttat ctaatcctac atgcccatgc tgcaatttgg aaagagagcg 2460

agttcctaac ctctgtagga acccccatta attaccacaa ggaaattata gagttattgc 2520

acgcaatgca aaaacacaaa gaggtcggaa tcttacactg tcaaagccat cagaatagga 2580

acgagagggg agaacagcag cataagcatc tggcagaggt agccgaaaga aaagaaagag 2640

acaggaagtc aaagaaagag acggagagga aaagacaaga agctaaagag aaagacggac 2700

agacacggta gtaaaagaca gggtaaataa gagacgaaga gagaaagaag atgtcaaaga 2760

gacagatgaa gtagtaaaga aaaaacaggt acctattcct ttaaaaccca gggtaaattt 2820

ctctctaccg acgcaaggca attctctatg tgatatcacc catatctgcc tctctaatag 2880

ttgaagaata atgaaatctg tccttacttt acaatccaaa atagacactt tggcagcagt 2940

gactcgccaa aaccgctgag gcatagatgt cctcactgct gaagaaagag gactctgcac 3000

tttcttaggg gaagagtgtt gttttgacac taaccaggca cggatagcat gagatggcac 3060

ccagcgttta cagaaaaagg ctgctgaaat gagtcgcctt ttaaattctt ataccaacct 3120

gtggtgtggg gcaacatggc ttctcacctt tctaggtccc gtggcaaccg tcttggtgtt 3180

actcgccttt gggcccagca tttttaacgt tcttgtcaaa tttgtttgtc tagattcgag 3240

gccttcaagc tacagatggt cttacatatc aaaccccgaa taatttcaac taactacttc 3300

tacggaggac acctggacta accagctggc agttaccctg gcctagagag ttcccctctg 3360

aaggtcacta caactgcaaa gccccttttt cgcgcctatc catcaggacg tacctagaac 3420

agtcctcggc catattgcca acagcagttg gagtgtcctg ttgattgagg ggtgacagca 3480

tgctggcagt cctcacagca ctaacgcgct cgctcacgct cggcacctcc tgtgtctggg 3540

ctcccacttt ggcagcactt gaggagccct tcagctcagt atctacctac tctgatgggt 3600

ccttcgagaa gctttatgtc tagctcaggg cttctaaata gaccaatcaa caccctgtgt 3660

ctagctcagg gcttgtgaat gcgcgaatgg ccacactgta tcttgctact ctagtggggc 3720

cttggagaac ctatgtgtca acgctctgga tctaactaac ctggtccgga tgtgccgaac 3780

cttagtgtct tgctcacgga tgtaaacgga ccaatcaatg ccctgtcaaa ccactcggct 3840

ctaccaatca gcaggatgtg ggtggggcca gataagacaa taacagcagg ctgcccgagc 3900

ctgccgtggc 3910

396

›DNA

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

cggagaaagc tccaaaagca agccctgggc cctgaacaaa atctggaggc attattaaac 60

ctggcaacct tagtgttcta taatagggtc cgagaggaac aggcccaaaa ggaaaagtga 120

gatcagagag aggccacagc cttagtcatg gccctcagac aaacaaacct tggtggttca 180

gagaggacag aaaatggatc aggccaatca cctggtaggg cttgttatca gtgtggttta 240

caaggacact ttaaaaaaga ttgtccaaca agaaacaagc caccccctca tccatgtccg 300

ctatgccgag ccaatcactg gaaggcacac tgccccagag tgaaatggtt ctctggccca 360

gaagccctca accagatgat ccaacaacag gactga 396

Arg Arg Lys Leu Gln Lys Gln Ala Leu Gly Pro Glu Gln Asn Leu Glu

1 5 10 15

Ala Leu Leu Asn Leu Ala Thr Leu Val Phe Tyr Asn Arg Val Arg Glu

20 25 30

Glu Gln Ala Gln Lys Glu Lys Xaa Asp Gln Arg Glu Ala Thr Ala Leu

35 40 45

Val Met Ala Leu Arg Gln Thr Asn Leu Gly Gly Ser Glu Arg Thr Glu

50 55 60

Asn Gly Ser Gly Gln Ser Pro Gly Arg Ala Cys Tyr Gln Cys Gly Leu

65 70 75 80

Gln Gly His Phe Lys Lys Asp Cys Pro Thr Arg Asn Lys Pro Pro Pro

85 90 95

His Pro Cys Pro Leu Cys Arg Ala Asn His Trp Lys Ala His Cys Pro

100 105 110

Arg Val Lys Trp Phe Ser Gly Pro Glu Ala Leu Asn Gln Met Ile Gln

115 120 125

Gln Gln Asp

130

2330

›DNA · 1 of 2

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

gagtgcctgg gccaagtgcc agctcatgtc atcaacctta ctgagtcccg ggtatgttta 60

accattgagg gccaggaaat tgacttcctc ctggacactg gcatggcctt ctcagtgtta 120

atctcctgtc ctggatgact gtcctcaagg tccattacca tccaaggaat cctaagacag 180

cctataacca ggtatttctc ccacctcctc agttgtaatt gggagacttt gctcttttca 240

catgcctttc ttgttatacc tgaaagtccc acacccttat tagggaggga tatattagcc 300

aaagctggag ctattaccta tatgaataag aggaacaagt taaccatttg ttgtcctcta 360

cttgaggagg gaatcaaccc tgaagtctgg gcattggaag gacaatttgg aagggcaaaa 420

aatgcctgcc cagtccaaat caggctaaaa gaccccacca cttttcctat caaaggcaat 480

atcccttaag gcctgaagct cataaaggat tacaggatat tgctagacat ttaatagctc 540

aaggcttagt aaggaaatgc agcagtccct gaaacacgcc aattctagga gtacaaaaac 600

cgaacggtca gtggagacta gtgcaagatc ttagactcac taatgacgca gtaattcctc 660

tatatccagt tgtacccaac ccctataccc tgctctctca aataccagag gaagcagaat 720

ggttcacagt tctggacttc aaggatgcct tcttctgtgt tcccctgcac tctgattcac 780

agctcctctt tgcttttgag gatcccacaa accacacatc ccaacttaca tggatggtct 840

tgccccaagg gtttagggat agccctcatc tgtttggtca ggccctagcc aaagatctaa 900

gccacttctc aggtccaggc actctggtcc ttcaatatgt ggatgattta cttttggcta 960

ccagttagga agccttgtgc cagcaggcta ctctagatct cttgaacctt ctagctaatc 1020

aagggtacaa ggtgtctatg ttcaaagccc aactttgcct acagcaggtt aaatatctag 1080

gcctaatctt agccaaaggg acaagggccc tcagcaagga atgaatacag cctatactgg 1140

cttatcctcg ccctaagaca ttaaaacagt tgagggagtt ccttggaatt accagctttt 1200

gccgactatg gatccctgga tacagcgaga cagccaggcc cctctaatca aggaaaccca 1260

gagggcaaat actcatctag ttgagtggga accagaggca gaaacaacct tcagaacctt 1320

aaagcaggct ctagtacaag ctccagcttt aagctttccc acaggacaga atttctcttt 1380

atatgtcaga gagagagcca ggatagctat tagagtcctc actcaaactc atcggactgc 1440

cccacgacca gtggcaaacc taagtaagga aattgatgta gtagcaaaag gctggcctca 1500

gtgtttaggg gtagttgcag ctgtggccgc cttagcatca gaggctatca aaataataca 1560

aggaaaggat ctcacagtct agactactta tgatgttaat ggcatactag gtgcccaagg 1620

aagtttatgg ctatcagata actgcctact tagataccag gcactactcc ttgagggaac 1680

agtacttaaa aaatgcacat gcatggccct taaccctgcc acttttctca cagaggatcg 1740

ggaacctatc aagcaggact gacaacaaat tatagtccag acttatgccg cccgagatga 1800

tctcttaaaa gtccccttaa ctaatccaga ccttaaccta tatactgatg gaagttcact 1860

tgtggaccat gcgatacgta ggttagttat gtaacgatac ttgaaaacaa gcctcttccg 1920

ccagggacca gtgcccagtt agcggaacta gtggcactta ccttggcctc agaagtggga 1980

tgggcaaaag aataaatttg tttagagata gcaggtatgc ttatctaatc ctacatgccc 2040

atgctgcaat ttggaaagag agcgagttcc taacctctgt aggaaccccc attaattacc 2100

acaaggaaat tatagagtta ttgcacgcaa tgcaaaaaca caaagaggtc ggaatcttac 2160

actgtcaaag ccatcagaat aggaacgaga ggggagaaca gcagcataag catctggcag 2220

aggtagccga aagaaaagaa agagacagga agtcaaagaa agagacggag aggaaaagac 2280

aagaagctaa agagaaagac ggacagacac ggtagtaaaa gacagggtaa 2330

Glu Cys Leu Gly Gln Val Pro Ala His Val Ile Asn Leu Thr Glu Ser

1 5 10 15

Arg Val Cys Leu Thr Ile Glu Gly Gln Glu Ile Asp Phe Leu Leu Asp

20 25 30

Thr Gly Met Ala Phe Ser Val Leu Ile Ser Cys Pro Gly Xaa Leu Ser

35 40 45

Ser Arg Ser Ile Thr Ile Gln Gly Ile Leu Arg Gln Pro Ile Thr Arg

50 55 60

Tyr Phe Ser His Leu Leu Ser Cys Asn Trp Glu Thr Leu Leu Phe Ser

65 70 75 80

His Ala Phe Leu Val Ile Pro Glu Ser Pro Thr Pro Leu Leu Gly Arg

85 90 95

Asp Ile Leu Ala Lys Ala Gly Ala Ile Thr Tyr Met Asn Lys Arg Asn

100 105 110

Lys Leu Thr Ile Cys Cys Pro Leu Leu Glu Arg Glu Ser Thr Leu Lys

115 120 125

Ser Gly His Trp Lys Asp Asn Leu Glu Gly Gln Lys Met Pro Ala Gln

130 135 140

Ser Lys Ser Gly Lys Arg Pro His His Phe Ser Tyr Gln Arg Gln Tyr

145 150 155 160

Pro Leu Arg Pro Glu Ala His Lys Gly Leu Gln Asp Ile Ala Glu His

165 170 175

Leu Ile Ala Gln Gly Leu Val Arg Lys Cys Ser Ser Pro Asn Thr Pro

180 185 190

Xaa Ile Leu Gly Val Gln Lys Pro Asn Gly Gln Trp Arg Leu Val Gln

195 200 205

Asp Leu Arg Leu Thr Asn Asp Ala Val Ile Pro Leu Tyr Pro Val Val

210 215 220

Pro Asn Pro Tyr Thr Leu Leu Ser Gln Ile Pro Glu Glu Ala Glu Trp

225 230 235 240

Phe Thr Val Leu Asp Phe Lys Asp Ala Phe Phe Cys Val Pro Leu His

245 250 255

Ser Asp Ser Gln Leu Leu Phe Ala Phe Glu Asp Pro Thr Asn His Thr

260 265 270

Ser Gln Leu Thr Trp Met Val Leu Pro Gln Gly Phe Arg Asp Ser Pro

275 280 285

His Leu Phe Gly Gln Ala Leu Ala Lys Asp Leu Ser His Phe Ser Gly

290 295 300

Pro Gly Thr Leu Val Leu Gln Tyr Val Asp Asp Leu Leu Leu Ala Thr

305 310 315 320

Ser Xaa Glu Ala Leu Cys Gln Gln Ala Thr Leu Asp Leu Leu Asn Leu

325 330 335

Leu Ala Asn Gln Gly Tyr Lys Val Ser Met Phe Lys Ala Gln Leu Cys

340 345 350

Leu Gln Gln Val Lys Tyr Leu Gly Leu Ile Leu Ala Lys Gly Thr Arg

355 360 365

Ala Leu Ser Lys Glu Xaa Ile Gln Pro Ile Leu Ala Tyr Pro Arg Pro

370 375 380

Lys Thr Leu Lys Gln Leu Arg Glu Phe Leu Gly Ile Thr Ser Phe Cys

385 390 395 400

Arg Leu Trp Ile Pro Gly Tyr Ser Glu Thr Ala Arg Pro Leu Ile Lys

405 410 415

Glu Thr Gln Arg Ala Asn Thr His Leu Val Glu Trp Glu Pro Glu Ala

420 425 430

Glu Thr Thr Phe Arg Thr Leu Lys Gln Ala Leu Val Gln Ala Pro Ala

435 440 445

Leu Ser Phe Pro Thr Gly Gln Asn Phe Ser Leu Tyr Val Arg Glu Arg

450 455 460

Ala Arg Ile Ala Ile Arg Val Leu Thr Gln Thr His Arg Thr Ala Pro

465 470 475 480

Arg Pro Val Ala Asn Leu Ser Lys Glu Ile Asp Val Val Ala Lys Gly

485 490 495

Trp Pro Gln Cys Leu Gly Val Val Ala Ala Val Ala Ala Leu Ala Ser

500 505 510

Glu Ala Ile Lys Ile Ile Gln Gly Lys Asp Leu Thr Val Xaa Thr Thr

515 520 525

Tyr Asp Val Asn Gly Ile Leu Gly Ala Gln Gly Ser Leu Trp Leu Ser

530 535 540

Asp Asn Cys Leu Leu Arg Tyr Gln Ala Leu Leu Leu Glu Gly Thr Val

545 550 555 560

Leu Lys Lys Cys Thr Cys Met Ala Leu Asn Pro Ala Thr Phe Leu Thr

565 570 575

Glu Asp Arg Glu Pro Ile Lys Gln Asp Xaa Gln Gln Ile Ile Val Gln

580 585 590

Thr Tyr Ala Ala Arg Asp Asp Leu Leu Lys Val Pro Leu Thr Asn Pro

595 600 605

Asp Leu Asn Leu Tyr Thr Asp Gly Ser Ser Leu Val Asp His Ala Ile

610 615 620

Arg Val Ser Tyr Val Thr Ile Leu Glu Asn Lys Pro Leu Pro Pro Gly

625 630 635 640

Thr Ser Ala Gln Leu Ala Glu Leu Val Ala Leu Thr Leu Ala Ser Glu

645 650 655

Val Gly Gly Lys Arg Ile Asn Leu Phe Arg Asp Ser Arg Tyr Ala Tyr

660 665 670

Leu Ile Leu His Ala His Ala Ala Ile Trp Lys Glu Ser Glu Phe Leu

675 680 685

Thr Ser Val Gly Thr Pro Ile Asn Tyr His Lys Glu Ile Ile Glu Leu

›DNA · 2 of 2

690 695 700

Leu His Ala Met Gln Lys His Lys Glu Val Gly Ile Leu His Cys Gln

705 710 715 720

Ser His Gln Asn Arg Asn Glu Arg Gly Glu Gln Gln His Lys His Leu

725 730 735

Ala Glu Val Ala Glu Arg Lys Glu Arg Asp Arg Lys Ser Lys Lys Glu

740 745 750

Thr Glu Arg Lys Arg Gln Glu Ala Lys Glu Lys Asp Gly Gln Thr Arg

755 760 765

464

›DNA

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUD ERV-9

acccatatct gcctctctaa tagttgaaga ataatgaaat ctgtccttac tttacaatcc 60

aaaatagaca ctttggcagc agtgactcgc caaaaccgct gaggcataga tgtcctcact 120

gctgaagaaa gaggactctg cactttctta ggggaagagt gttgttttga cactaaccag 180

gcacggatag catgagatgg cacccagcgt ttacagaaaa aggctgctga aatgagtcgc 240

cttttaaatt cttataccaa cctgtggtgt ggggcaacat ggcttctcac ctttctaggt 300

cccgtggcaa ccgtcttggt gttactcgcc tttgggccca gcatttttaa cgttcttgtc 360

aaatttgttt gtctagattc gaggccttca agctacagat ggtcttacat atcaaacccc 420

gaataatttc aactaactac ttctacggag gacacctgga ctaa 464

Thr His Ile Cys Leu Ser Asn Ser Glu Glu Met Lys Ser Val Leu Thr

1 5 10 15

Leu Gln Ser Lys Ile Asp Thr Leu Ala Ala Val Thr Arg Gln Asn Arg

20 25 30

Xaa Gly Ile Asp Val Leu Thr Ala Glu Glu Arg Gly Leu Cys Thr Phe

35 40 45

Leu Gly Glu Glu Cys Cys Phe Asp Thr Asn Gln Ala Arg Ile Ala Xaa

50 55 60

Asp Gly Thr Gln Arg Leu Gln Lys Lys Ala Ala Glu Met Ser Arg Leu

65 70 75 80

Leu Asn Ser Tyr Thr Asn Leu Trp Cys Gly Ala Thr Trp Leu Leu Thr

85 90 95

Phe Leu Gly Pro Val Ala Thr Val Leu Val Leu Leu Ala Phe Gly Pro

100 105 110

Ser Ile Phe Asn Val Leu Val Lys Phe Val Ser Arg Phe Glu Ala Phe

115 120 125

Lys Leu Gln Met Val Leu His Ile Lys Pro Arg Ile Ile Ser Thr Asn

130 135 140

Tyr Phe Tyr Gly Gly His Leu Asp

145 150

›PRT

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Arg Arg Lys Leu Gln Lys Gln Ala Leu Gly Pro Glu Gln Asn Leu Glu

1 5 10 15

Arg Val Arg Glu Glu Gln Ala Gln Lys Glu Lys Xaa Asp Gln Arg Glu

1 5 10 15

›PRT

DIABETS-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Gly Gly Ser Glu Arg Thr Glu Asn Gly Ser Gly Gln Ser Pro Gly Arg

1 5 10 15

Ala Cys

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Lys Lys Asp Cys Pro Thr Arg Asn Lys Pro Pro Pro His Pro Cys Pro

1 5 10 15

Leu Cys Arg Ala Asn His Trp Lys

›PRT

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Glu Arg Glu Ser Thr Leu Lys Ser Gly His Trp Lys Asp Asn Leu Glu

1 5 10 15

Gly Gln Lys Met Pro Ala Gln Ser Lys Ser Gly Lys Arg Pro His His

20 25 30

›PRT

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Ser Tyr Gln Arg Gln Tyr Pro Leu Arg Pro Glu Ala His Lys Gly Leu

1 5 10 15

Gln Asp Ile Ala Glu His

Gly Leu Val Arg Lys Cys Ser Ser Pro Xaa Asn Thr Pro Ile Leu Gly

1 5 10 15

Val Gln Lys Pro Asn Gly Gln Trp Arg

20 25

›PRT

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

His Ser Asp Ser Gln Leu Leu Phe Ala Phe Glu Asp Pro Thr Asn His

1 5 10 15

Thr Ser Gln Leu Thr Trp

›PRT

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Arg Asp Ser Pro His Leu Phe Gly Gln Ala Leu Ala Lys Asp Leu Ser

1 5 10 15

His Phe Ser Gly Pro Gly

›PRT

DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Lys Asp Leu Ser His Phe Ser Gly Pro Gly Thr Leu Val Leu Gln Tyr

1 5 10 15

Ser Lys Glu Xaa Ile Gln Pro Ile Leu Ala Tyr Pro Arg Pro Lys Thr

1 5 10 15

Leu Lys Gln Leu Arg Glu

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Arg Pro Leu Ile Lys Glu Thr Gln Arg Ala Asn Thr His Leu Val Glu

1 5 10 15

Trp Glu Pro Glu Ala Glu Thr Thr Phe Arg Thr Leu Lys Gln

20 25 30

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Arg Val Leu Thr Gln Thr His Arg Thr Ala Pro Arg Pro Val Ala Asn

1 5 10 15

Leu Ser Lys Glu Ile Asp

Asn Pro Ala Thr Phe Leu Thr Glu Asp Arg Glu Pro Ile Lys Gln Asp

1 5 10 15

Xaa Gln Gln Ile Ile Val Gln

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Arg Asp Asp Leu Leu Lys Val Pro Leu Thr Asn Pro Asp Leu Asn Leu

1 5 10 15

Tyr Thr Asp Gly Ser Ser

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Ser Glu Val Gly Gly Lys Arg Ile Asn Leu Phe Arg Asp Ser Arg

1 5 10 15

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Gly Ile Leu His Cys Gln Ser His Gln Asn Arg Asn Glu Arg Gly Glu

1 5 10 15

Gln Gln His Lys His

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Glu Val Ala Glu Arg Lys Glu Arg Asp Arg Lys Ser Lys Lys Glu Thr

1 5 10 15

Glu Arg Lys Arg Gln Glu Ala Lys Glu Lys Asp Gly Gln Thr Arg

20 25 30

›PRT

DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Ser Asn Ser Glu Glu Met Lys Ser Val Leu Thr Leu Gln Ser Lys Ile

1 5 10 15

Asp

Gly Glu Glu Cys Cys Phe Asp Thr Asn Gln Ala Arg Ile Ala Xaa Asp

1 5 10 15

Gly Thr Gln Arg Leu Gln Lys Lys Ala Ala Glu Met Ser Arg

20 25 30

›PRT

DIIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9

Phe Val Ser Arg Phe Glu Ala Phe Lys Leu Gln Met Val Leu His Ile

1 5 10 15

Lys Pro Arg Ile Ile Ser Thr Asn Tyr Phe Tyr Gly Gly His Leu Asp

20 25 30

›Tables in the description — 8

3	131	PRT	DIABETES-SPECIFIC RETROVIRUS ENDOGENOUS ERV-9
NON_CONS	(40)	any one of 20 amino acids

5	768	PRT	DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9
NON_CONS	(46)	any one of amino acids

7	152	PRT	DIABETES-SPECIFIC ENDOGENOUS RETEOVIRUS ERV-9
NON_CONS	(33)	any one of amino acids

9	16	PRT	DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9
NON_CONS	(12)	any one of amino acids

14	25	PRT	DIABETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9
NON_CONS	(10)	any one of amino acids

18	22	PRT	DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9
NON_CONS	(4)	any one of amino acids

21	23	PRT	DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9
NON_CONS	(17)	any one of amino acids

27	30	PRT	DIEBETES-SPECIFIC ENDOGENOUS RETROVIRUS ERV-9
NON_CONS	(15)	any one of amino acids

Claims as granted

4 claims

Classifications

4 codes

IPC · International Patent Classification

Section C — Chemistry; metallurgy

C12Q1/70

USPC · US Patent Classification

536/23.72424/207.1424/187.1

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Examiner

Laurie Scheiner

art unit 1648 · TC 1600

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