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. 1996 Jan;70(1):232–240. doi: 10.1128/jvi.70.1.232-240.1996

Use of recombinant protein to identify a motif-negative human cytotoxic T-cell epitope presented by HLA-A2 in the hepatitis C virus NS3 region.

K Kurokohchi 1, T Akatsuka 1, C D Pendleton 1, A Takamizawa 1, M Nishioka 1, M Battegay 1, S M Feinstone 1, J A Berzofsky 1
PMCID: PMC189809  PMID: 8523531

Abstract

To define cytotoxic T-cell (CTL) epitopes, the common approach involving the use of a series of overlapping synthetic peptides covering the whole protein sequence is impractical for large proteins. Motifs identify only a fraction of epitopes. To identify human CTL epitopes in the NS3 region of hepatitis C virus (HCV), we modified an approach using recombinant protein and the ability of short peptides to bind to class I major histocompatibility complex (MHC) molecules. Peripheral blood mononuclear cells from an HCV-infected patient were stimulated with a proteolytic digest of the recombinant NS3 protein to expand CTL to any active peptides in the digest. The digest was fractionated by reverse-phase high-performance liquid chromatography, and fractions were assessed for the ability to sensitize targets for lysis by CTL. The most active fraction was sequenced, identifying a 15-residue peptide (NS3-1J; TITTGAPVTYSTYGK). This sequence was confirmed to be the source of the activity by synthesis of the corresponding peptide. CTL lines specific for NS3-1J were established from two HCV-infected patients (both HLA-A2 and -B7 positive) by stimulation with the synthetic peptide in vitro. The CTL were HLA-A2 restricted, and the minimal epitope was mapped to a decapeptide NS3-1J (10.4). As this minimal epitope lacks the common HLA-A2-binding motif, this technique is useful for mapping CTL epitopes independent of known motifs and without the requirement for enormous numbers of overlapping peptides. Because this peptide is presented by the most common HLA class I molecule, present in almost half the population, it might be a useful component of a vaccine against HCV.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Achour A., Picard O., Mbika J. P., Willer A., Snart R., Bizzini B., Carelli C., Burny A., Zagury D. Envelope protein and p18(IIIB) peptide recognized by cytotoxic T lymphocytes from humans immunized with human immunodeficiency virus envelope. Vaccine. 1993;11(7):609–701. doi: 10.1016/0264-410x(93)90251-r. [DOI] [PubMed] [Google Scholar]
  2. Alter H. J., Purcell R. H., Shih J. W., Melpolder J. C., Houghton M., Choo Q. L., Kuo G. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med. 1989 Nov 30;321(22):1494–1500. doi: 10.1056/NEJM198911303212202. [DOI] [PubMed] [Google Scholar]
  3. Battegay M., Fikes J., Di Bisceglie A. M., Wentworth P. A., Sette A., Celis E., Ching W. M., Grakoui A., Rice C. M., Kurokohchi K. Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules. J Virol. 1995 Apr;69(4):2462–2470. doi: 10.1128/jvi.69.4.2462-2470.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bradley D. W., McCaustland K. A., Cook E. H., Schable C. A., Ebert J. W., Maynard J. E. Posttransfusion non-A, non-B hepatitis in chimpanzees. Physicochemical evidence that the tubule-forming agent is a small, enveloped virus. Gastroenterology. 1985 Mar;88(3):773–779. [PubMed] [Google Scholar]
  5. Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carbone F. R., Moore M. W., Sheil J. M., Bevan M. J. Induction of cytotoxic T lymphocytes by primary in vitro stimulation with peptides. J Exp Med. 1988 Jun 1;167(6):1767–1779. doi: 10.1084/jem.167.6.1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cease K. B., Berzofsky J. A. Toward a vaccine for AIDS: the emergence of immunobiology-based vaccine development. Annu Rev Immunol. 1994;12:923–989. doi: 10.1146/annurev.iy.12.040194.004423. [DOI] [PubMed] [Google Scholar]
  8. Cerny A., Ferrari C., Chisari F. V. The class I-restricted cytotoxic T lymphocyte response to predetermined epitopes in the hepatitis B and C viruses. Curr Top Microbiol Immunol. 1994;189:169–186. doi: 10.1007/978-3-642-78530-6_10. [DOI] [PubMed] [Google Scholar]
  9. Choo Q. L., Kuo G., Weiner A. J., Overby L. R., Bradley D. W., Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989 Apr 21;244(4902):359–362. doi: 10.1126/science.2523562. [DOI] [PubMed] [Google Scholar]
  10. Choo Q. L., Richman K. H., Han J. H., Berger K., Lee C., Dong C., Gallegos C., Coit D., Medina-Selby R., Barr P. J. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2451–2455. doi: 10.1073/pnas.88.6.2451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Collett M. S., Anderson D. K., Retzel E. Comparisons of the pestivirus bovine viral diarrhoea virus with members of the flaviviridae. J Gen Virol. 1988 Oct;69(Pt 10):2637–2643. doi: 10.1099/0022-1317-69-10-2637. [DOI] [PubMed] [Google Scholar]
  12. Cristiano K., Di Bisceglie A. M., Hoofnagle J. H., Feinstone S. M. Hepatitis C viral RNA in serum of patients with chronic non-A, non-B hepatitis: detection by the polymerase chain reaction using multiple primer sets. Hepatology. 1991 Jul;14(1):51–55. doi: 10.1002/hep.1840140109. [DOI] [PubMed] [Google Scholar]
  13. Di Bisceglie A. M., Hoofnagle J. H. Therapy of chronic hepatitis C with alpha-interferon: the answer? Or more questions? Hepatology. 1991 Mar;13(3):601–603. doi: 10.1016/0270-9139(91)90318-p. [DOI] [PubMed] [Google Scholar]
  14. Dick L. R., Aldrich C., Jameson S. C., Moomaw C. R., Pramanik B. C., Doyle C. K., DeMartino G. N., Bevan M. J., Forman J. M., Slaughter C. A. Proteolytic processing of ovalbumin and beta-galactosidase by the proteasome to a yield antigenic peptides. J Immunol. 1994 Apr 15;152(8):3884–3894. [PMC free article] [PubMed] [Google Scholar]
  15. Earl P. L., Moss B., Morrison R. P., Wehrly K., Nishio J., Chesebro B. T-lymphocyte priming and protection against Friend leukemia by vaccinia-retrovirus env gene recombinant. Science. 1986 Nov 7;234(4777):728–731. doi: 10.1126/science.3490689. [DOI] [PubMed] [Google Scholar]
  16. Erickson A. L., Houghton M., Choo Q. L., Weiner A. J., Ralston R., Muchmore E., Walker C. M. Hepatitis C virus-specific CTL responses in the liver of chimpanzees with acute and chronic hepatitis C. J Immunol. 1993 Oct 15;151(8):4189–4199. [PubMed] [Google Scholar]
  17. Esteban J. I., Esteban R., Viladomiu L., López-Talavera J. C., González A., Hernández J. M., Roget M., Vargas V., Genescà J., Buti M. Hepatitis C virus antibodies among risk groups in Spain. Lancet. 1989 Aug 5;2(8658):294–297. doi: 10.1016/s0140-6736(89)90485-6. [DOI] [PubMed] [Google Scholar]
  18. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  19. Feinstone S. M., Alter H. J., Dienes H. P., Shimizu Y., Popper H., Blackmore D., Sly D., London W. T., Purcell R. H. Non-A, non-B hepatitis in chimpanzees and marmosets. J Infect Dis. 1981 Dec;144(6):588–598. doi: 10.1093/infdis/144.6.588. [DOI] [PubMed] [Google Scholar]
  20. Fields G. B., Noble R. L. Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res. 1990 Mar;35(3):161–214. doi: 10.1111/j.1399-3011.1990.tb00939.x. [DOI] [PubMed] [Google Scholar]
  21. Gavin M. A., Gilbert M. J., Riddell S. R., Greenberg P. D., Bevan M. J. Alkali hydrolysis of recombinant proteins allows for the rapid identification of class I MHC-restricted CTL epitopes. J Immunol. 1993 Oct 15;151(8):3971–3980. [PubMed] [Google Scholar]
  22. Germain R. N., Margulies D. H. The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol. 1993;11:403–450. doi: 10.1146/annurev.iy.11.040193.002155. [DOI] [PubMed] [Google Scholar]
  23. Goodman J. W., Sercarz E. E. The complexity of structures involved in T-cell activation. Annu Rev Immunol. 1983;1:465–498. doi: 10.1146/annurev.iy.01.040183.002341. [DOI] [PubMed] [Google Scholar]
  24. Grakoui A., McCourt D. W., Wychowski C., Feinstone S. M., Rice C. M. A second hepatitis C virus-encoded proteinase. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10583–10587. doi: 10.1073/pnas.90.22.10583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Grakoui A., McCourt D. W., Wychowski C., Feinstone S. M., Rice C. M. Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J Virol. 1993 May;67(5):2832–2843. doi: 10.1128/jvi.67.5.2832-2843.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Grakoui A., Wychowski C., Lin C., Feinstone S. M., Rice C. M. Expression and identification of hepatitis C virus polyprotein cleavage products. J Virol. 1993 Mar;67(3):1385–1395. doi: 10.1128/jvi.67.3.1385-1395.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. He L. F., Alling D., Popkin T., Shapiro M., Alter H. J., Purcell R. H. Determining the size of non-A, non-B hepatitis virus by filtration. J Infect Dis. 1987 Oct;156(4):636–640. doi: 10.1093/infdis/156.4.636. [DOI] [PubMed] [Google Scholar]
  28. Heath W. R., Kane K. P., Mescher M. F., Sherman L. A. Alloreactive T cells discriminate among a diverse set of endogenous peptides. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5101–5105. doi: 10.1073/pnas.88.12.5101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Henderson R. A., Michel H., Sakaguchi K., Shabanowitz J., Appella E., Hunt D. F., Engelhard V. H. HLA-A2.1-associated peptides from a mutant cell line: a second pathway of antigen presentation. Science. 1992 Mar 6;255(5049):1264–1266. doi: 10.1126/science.1546329. [DOI] [PubMed] [Google Scholar]
  30. Hijikata M., Mizushima H., Akagi T., Mori S., Kakiuchi N., Kato N., Tanaka T., Kimura K., Shimotohno K. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol. 1993 Aug;67(8):4665–4675. doi: 10.1128/jvi.67.8.4665-4675.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hijikata M., Mizushima H., Tanji Y., Komoda Y., Hirowatari Y., Akagi T., Kato N., Kimura K., Shimotohno K. Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10773–10777. doi: 10.1073/pnas.90.22.10773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hou S., Doherty P. C., Zijlstra M., Jaenisch R., Katz J. M. Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J Immunol. 1992 Aug 15;149(4):1319–1325. [PubMed] [Google Scholar]
  33. Houghton M., Weiner A., Han J., Kuo G., Choo Q. L. Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral disease. Hepatology. 1991 Aug;14(2):381–388. [PubMed] [Google Scholar]
  34. Houmard J., Drapeau G. R. Staphylococcal protease: a proteolytic enzyme specific for glutamoyl bonds. Proc Natl Acad Sci U S A. 1972 Dec;69(12):3506–3509. doi: 10.1073/pnas.69.12.3506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hunt D. F., Henderson R. A., Shabanowitz J., Sakaguchi K., Michel H., Sevilir N., Cox A. L., Appella E., Engelhard V. H. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science. 1992 Mar 6;255(5049):1261–1263. doi: 10.1126/science.1546328. [DOI] [PubMed] [Google Scholar]
  36. Imawari M., Nomura M., Kaieda T., Moriyama T., Oshimi K., Nakamura I., Gunji T., Ohnishi S., Ishikawa T., Nakagama H. Establishment of a human T-cell clone cytotoxic for both autologous and allogeneic hepatocytes from chronic hepatitis patients with type non-A, non-B virus. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2883–2887. doi: 10.1073/pnas.86.8.2883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Inchauspe G., Zebedee S., Lee D. H., Sugitani M., Nasoff M., Prince A. M. Genomic structure of the human prototype strain H of hepatitis C virus: comparison with American and Japanese isolates. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10292–10296. doi: 10.1073/pnas.88.22.10292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kast W. M., Brandt R. M., Drijfhout J. W., Melief C. J. Human leukocyte antigen-A2.1 restricted candidate cytotoxic T lymphocyte epitopes of human papillomavirus type 16 E6 and E7 proteins identified by using the processing-defective human cell line T2. J Immunother Emphasis Tumor Immunol. 1993 Aug;14(2):115–120. doi: 10.1097/00002371-199308000-00006. [DOI] [PubMed] [Google Scholar]
  39. Kast W. M., Brandt R. M., Sidney J., Drijfhout J. W., Kubo R. T., Grey H. M., Melief C. J., Sette A. Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. J Immunol. 1994 Apr 15;152(8):3904–3912. [PubMed] [Google Scholar]
  40. Kast W. M., Offringa R., Peters P. J., Voordouw A. C., Meloen R. H., van der Eb A. J., Melief C. J. Eradication of adenovirus E1-induced tumors by E1A-specific cytotoxic T lymphocytes. Cell. 1989 Nov 17;59(4):603–614. doi: 10.1016/0092-8674(89)90006-8. [DOI] [PubMed] [Google Scholar]
  41. Kita H., Moriyama T., Kaneko T., Harase I., Nomura M., Miura H., Nakamura I., Yazaki Y., Imawari M. HLA B44-restricted cytotoxic T lymphocytes recognizing an epitope on hepatitis C virus nucleocapsid protein. Hepatology. 1993 Nov;18(5):1039–1044. [PubMed] [Google Scholar]
  42. Kiyosawa K., Sodeyama T., Tanaka E., Gibo Y., Yoshizawa K., Nakano Y., Furuta S., Akahane Y., Nishioka K., Purcell R. H. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology. 1990 Oct;12(4 Pt 1):671–675. doi: 10.1002/hep.1840120409. [DOI] [PubMed] [Google Scholar]
  43. Klavinskis L. S., Tishon A., Oldstone M. B. Efficiency and effectiveness of cloned virus-specific cytotoxic T lymphocytes in vivo. J Immunol. 1989 Sep 15;143(6):2013–2016. [PubMed] [Google Scholar]
  44. Koziel M. J., Dudley D., Afdhal N., Choo Q. L., Houghton M., Ralston R., Walker B. D. Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV. J Virol. 1993 Dec;67(12):7522–7532. doi: 10.1128/jvi.67.12.7522-7532.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Koziel M. J., Dudley D., Wong J. T., Dienstag J., Houghton M., Ralston R., Walker B. D. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol. 1992 Nov 15;149(10):3339–3344. [PubMed] [Google Scholar]
  46. Kozlowski S., Corr M., Takeshita T., Boyd L. F., Pendleton C. D., Germain R. N., Berzofsky J. A., Margulies D. H. Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules. J Exp Med. 1992 Jun 1;175(6):1417–1422. doi: 10.1084/jem.175.6.1417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. doi: 10.1126/science.2496467. [DOI] [PubMed] [Google Scholar]
  48. Kurane I., Brinton M. A., Samson A. L., Ennis F. A. Dengue virus-specific, human CD4+ CD8- cytotoxic T-cell clones: multiple patterns of virus cross-reactivity recognized by NS3-specific T-cell clones. J Virol. 1991 Apr;65(4):1823–1828. doi: 10.1128/jvi.65.4.1823-1828.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Lampson L. A., Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed] [Google Scholar]
  50. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Lipford G. B., Hoffman M., Wagner H., Heeg K. Primary in vivo responses to ovalbumin. Probing the predictive value of the Kb binding motif. J Immunol. 1993 Feb 15;150(4):1212–1222. [PubMed] [Google Scholar]
  52. Manabe S., Fuke I., Tanishita O., Kaji C., Gomi Y., Yoshida S., Mori C., Takamizawa A., Yosida I., Okayama H. Production of nonstructural proteins of hepatitis C virus requires a putative viral protease encoded by NS3. Virology. 1994 Feb;198(2):636–644. doi: 10.1006/viro.1994.1075. [DOI] [PubMed] [Google Scholar]
  53. Mitchell L. C., Davis L. S., Lipsky P. E. Promotion of human T lymphocyte proliferation by IL-4. J Immunol. 1989 Mar 1;142(5):1548–1557. [PubMed] [Google Scholar]
  54. Mondelli M., Vergani G. M., Alberti A., Vergani D., Portmann B., Eddleston A. L., Williams R. Specificity of T lymphocyte cytotoxicity to autologous hepatocytes in chronic hepatitis B virus infection: evidence that T cells are directed against HBV core antigen expressed on hepatocytes. J Immunol. 1982 Dec;129(6):2773–2778. [PubMed] [Google Scholar]
  55. Moore M. W., Carbone F. R., Bevan M. J. Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell. 1988 Sep 9;54(6):777–785. doi: 10.1016/s0092-8674(88)91043-4. [DOI] [PubMed] [Google Scholar]
  56. Naumov N. V., Mondelli M., Alexander G. J., Tedder R. S., Eddleston A. L., Williams R. Relationship between expression of hepatitis B virus antigens in isolated hepatocytes and autologous lymphocyte cytotoxicity in patients with chronic hepatitis B virus infection. Hepatology. 1984 Jan-Feb;4(1):63–68. doi: 10.1002/hep.1840040111. [DOI] [PubMed] [Google Scholar]
  57. Newberg M. H., Ridge J. P., Vining D. R., Salter R. D., Engelhard V. H. Species specificity in the interaction of CD8 with the alpha 3 domain of MHC class I molecules. J Immunol. 1992 Jul 1;149(1):136–142. [PubMed] [Google Scholar]
  58. Pamer E. G., Harty J. T., Bevan M. J. Precise prediction of a dominant class I MHC-restricted epitope of Listeria monocytogenes. Nature. 1991 Oct 31;353(6347):852–855. doi: 10.1038/353852a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Plata F., Langlade-Demoyen P., Abastado J. P., Berbar T., Kourilsky P. Retrovirus antigens recognized by cytolytic T lymphocytes activate tumor rejection in vivo. Cell. 1987 Jan 30;48(2):231–240. doi: 10.1016/0092-8674(87)90426-0. [DOI] [PubMed] [Google Scholar]
  60. Rothman A. L., Kurane I., Lai C. J., Bray M., Falgout B., Men R., Ennis F. A. Dengue virus protein recognition by virus-specific murine CD8+ cytotoxic T lymphocytes. J Virol. 1993 Feb;67(2):801–806. doi: 10.1128/jvi.67.2.801-806.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Saito I., Miyamura T., Ohbayashi A., Harada H., Katayama T., Kikuchi S., Watanabe Y., Koi S., Onji M., Ohta Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6547–6549. doi: 10.1073/pnas.87.17.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Schulz M., Zinkernagel R. M., Hengartner H. Peptide-induced antiviral protection by cytotoxic T cells. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):991–993. doi: 10.1073/pnas.88.3.991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Sherman L. A., Burke T. A., Biggs J. A. Extracellular processing of peptide antigens that bind class I major histocompatibility molecules. J Exp Med. 1992 May 1;175(5):1221–1226. doi: 10.1084/jem.175.5.1221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Shimonkevitz R., Colon S., Kappler J. W., Marrack P., Grey H. M. Antigen recognition by H-2-restricted T cells. II. A tryptic ovalbumin peptide that substitutes for processed antigen. J Immunol. 1984 Oct;133(4):2067–2074. [PubMed] [Google Scholar]
  65. Shirai M., Arichi T., Nishioka M., Nomura T., Ikeda K., Kawanishi K., Engelhard V. H., Feinstone S. M., Berzofsky J. A. CTL responses of HLA-A2.1-transgenic mice specific for hepatitis C viral peptides predict epitopes for CTL of humans carrying HLA-A2.1. J Immunol. 1995 Mar 15;154(6):2733–2742. [PubMed] [Google Scholar]
  66. Shirai M., Okada H., Nishioka M., Akatsuka T., Wychowski C., Houghten R., Pendleton C. D., Feinstone S. M., Berzofsky J. A. An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans. J Virol. 1994 May;68(5):3334–3342. doi: 10.1128/jvi.68.5.3334-3342.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Simmonds P., Holmes E. C., Cha T. A., Chan S. W., McOmish F., Irvine B., Beall E., Yap P. L., Kolberg J., Urdea M. S. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol. 1993 Nov;74(Pt 11):2391–2399. doi: 10.1099/0022-1317-74-11-2391. [DOI] [PubMed] [Google Scholar]
  68. Sinigaglia F., Guttinger M., Kilgus J., Doran D. M., Matile H., Etlinger H., Trzeciak A., Gillessen D., Pink J. R. A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules. Nature. 1988 Dec 22;336(6201):778–780. doi: 10.1038/336778a0. [DOI] [PubMed] [Google Scholar]
  69. Takamizawa A., Mori C., Fuke I., Manabe S., Murakami S., Fujita J., Onishi E., Andoh T., Yoshida I., Okayama H. Structure and organization of the hepatitis C virus genome isolated from human carriers. J Virol. 1991 Mar;65(3):1105–1113. doi: 10.1128/jvi.65.3.1105-1113.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Taylor P. M., Askonas B. A. Influenza nucleoprotein-specific cytotoxic T-cell clones are protective in vivo. Immunology. 1986 Jul;58(3):417–420. [PMC free article] [PubMed] [Google Scholar]
  71. Tomei L., Failla C., Santolini E., De Francesco R., La Monica N. NS3 is a serine protease required for processing of hepatitis C virus polyprotein. J Virol. 1993 Jul;67(7):4017–4026. doi: 10.1128/jvi.67.7.4017-4026.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Tsubota H., Lord C. I., Watkins D. I., Morimoto C., Letvin N. L. A cytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. J Exp Med. 1989 Apr 1;169(4):1421–1434. doi: 10.1084/jem.169.4.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Vitiello A., Marchesini D., Furze J., Sherman L. A., Chesnut R. W. Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J Exp Med. 1991 Apr 1;173(4):1007–1015. doi: 10.1084/jem.173.4.1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Walker C. M., Moody D. J., Stites D. P., Levy J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. doi: 10.1126/science.2431484. [DOI] [PubMed] [Google Scholar]
  75. Weiner A. J., Geysen H. M., Christopherson C., Hall J. E., Mason T. J., Saracco G., Bonino F., Crawford K., Marion C. D., Crawford K. A. Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3468–3472. doi: 10.1073/pnas.89.8.3468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. van der Poel C. L., Reesink H. W., Lelie P. N., Leentvaar-Kuypers A., Choo Q. L., Kuo G., Houghton M. Anti-hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in The Netherlands. Lancet. 1989 Aug 5;2(8658):297–298. doi: 10.1016/s0140-6736(89)90486-8. [DOI] [PubMed] [Google Scholar]

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