1887

Abstract

The human leukocyte antigen (HLA)-A*2402 is common in Asians. The authors attempted to identify epitopes for HLA-A*2402-restricted, hepatitis C virus (HCV)-specific CD8 T cells by an enzyme-linked immunospot (ELISpot) assay using peripheral blood CD8 T cells from HLA-A*2402-positive hepatitis C patients and synthetic HCV peptides based on HLA-A*2402-binding motifs and the amino acid sequence of type 1b HCV. Ten novel epitopes were identified in five of seven HLA-A*2402-positive patients with acute or short-term chronic HCV infection (<3 years), but in none of four with longer-term chronic infection (>10 years). Only one of the ten epitopes proved to be definitely HLA-A*2402-restricted. Another epitope was identified in one of two HLA-A*2402-negative acute hepatitis C patients. In two of the six patients with positive CD8 T cell responses, the targeted epitopes were multiple. The same epitope was targeted in two patients. When patients with unresolved acute HCV infection were treated with alpha interferon, peripheral blood HCV-specific CD8 T cells decreased with resolution of the hepatitis. In conclusion, CD8 T cell responses to HCV infection are heterogeneous. One definite HLA-A*2402-restricted and ten probably non-HLA-A*2402-restricted epitopes were identified. Patients with short-term HCV infection are suitable for searching for novel HCV epitopes, but peripheral blood HCV-specific CD8 T cells decrease markedly after loss of antigenic stimulation.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.79801-0
2004-06-01
2020-04-02
Loading full text...

Full text loading...

/deliver/fulltext/jgv/85/6/vir851521.html?itemId=/content/journal/jgv/10.1099/vir.0.79801-0&mimeType=html&fmt=ahah

References

  1. Altfeld M. A., Trocha A., Eldridge R. L. 9 other authors; 2000; Identification of dominant optimal HLA-B60- and HLA-B61-restricted cytotoxic T-lymphocyte (CTL) epitopes: rapid characterization of CTL responses by enzyme-linked immunospot assay. J Virol 74:8541–8549 [CrossRef]
    [Google Scholar]
  2. Anthony D. D., Valdez H., Post A. B., Carlson N. L., Heeger P. S., Lehmann P. V. 2002; Comprehensive determinant mapping of the hepatitis C-specific CD8 cell repertoire reveals unpredicted immune hierarchy. Clin Immunol 103:264–276 [CrossRef]
    [Google Scholar]
  3. Barnes E., Harcourt G., Brown D., Lucas M., Phillips R., Dusheiko G., Klenerman P. 2002; The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 36:743–754 [CrossRef]
    [Google Scholar]
  4. Cannon M. J., Openshaw P. J., Askonas B. A. 1988; Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 168:1163–1168 [CrossRef]
    [Google Scholar]
  5. Cerny A., Chisari F. V. 1999; Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 30:595–601 [CrossRef]
    [Google Scholar]
  6. Chandanayingyong D. 1986; HLA in Asia–Oceania 1986. In Proceeding of the Third Asia–Oceania Histocompatibility Workshop and Conference pp  30–34 Edited by Aizawa M. Sapporo: Hokkaido University Press;
    [Google Scholar]
  7. Chisari F. V. 1997; Cytotoxic T cells and viral hepatitis. J Clin Invest 99:1472–1477 [CrossRef]
    [Google Scholar]
  8. Date Y., Kimura A., Kato H., Sasazuki T. 1996; DNA typing of the HLA-A gene: population study and identification of four new alleles in Japanese. Tissue Antigens 47:93–101 [CrossRef]
    [Google Scholar]
  9. Day C. L., Shea A. K., Altfeld M. A., Olson D. P., Buchbinder S. P., Hecht F. M., Rosenberg E. S., Walker B. D., Kalams S. A. 2001; Relative dominance of epitope-specific cytotoxic T-lymphocyte responses in human immunodeficiency virus type 1-infected persons with shared HLA alleles. J Virol 75:6279–6291 [CrossRef]
    [Google Scholar]
  10. Gotch F., Rothbard J., Howland K., Townsend A., McMichael A. 1987; Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. Nature 326:881–882 [CrossRef]
    [Google Scholar]
  11. Greten T. F., Slansky J. E., Kubota R., Soldan S. S., Jaffee E. M., Leist T. P., Pardoll D. M., Jacobson S., Schneck J. P. 1998; Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19-specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc Natl Acad Sci U S A 95:7568–7573 [CrossRef]
    [Google Scholar]
  12. Gruener N. H., Lechner F., Jung M. C. 8 other authors 2001; Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 75:5550–5558 [CrossRef]
    [Google Scholar]
  13. He X. S., Rehermann B., Lopez-Labrador F. X. 8 other authors 1999; Quantitative analysis of hepatitis C virus-specific CD8+ T cells in peripheral blood and liver using peptide-MHC tetramers. Proc Natl Acad Sci U S A 96:5692–5697 [CrossRef]
    [Google Scholar]
  14. Hiroishi K., Kita H., Kojima M. 10 other authors 1997; Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection. Hepatology 25:705–712 [CrossRef]
    [Google Scholar]
  15. Hiroishi K., Eguchi J., Ishi S., Okamoto H., Mitamura K., Imawari M. 2002; Differential effect of cytotoxic T lymphocyte variant epitopes on generation and cytotoxicity in chronic hepatitis C virus infection. Hepatol Res 24:91–94 [CrossRef]
    [Google Scholar]
  16. Ibe M., Moore Y. I., Miwa K., Kaneko Y., Yokota S., Takiguchi M. 1996; Role of strong anchor residues in the effective binding of 10-mer and 11-mer peptides to HLA-A*2402 molecules. Immunogenetics 44:233–241 [CrossRef]
    [Google Scholar]
  17. Ibe M., Sakaguchi T., Tanaka K. 9 other authors 1998; Identification and characterization of a cytotoxic T cell epitope of hepatitis C virus presented by HLA-B*3501 in acute hepatitis. J Gen Virol 79:1735–1744
    [Google Scholar]
  18. Ito A., Kanto T., Kuzushita N. 12 other authors 2001; Generation of hepatitis C virus-specific cytotoxic T lymphocytes from healthy individuals with peptide-pulsed dendritic cells. J Gastroenterol Hepatol 16:309–316 [CrossRef]
    [Google Scholar]
  19. Kurokohchi K., Arima K., Nishioka M. 2001; A novel cytotoxic T-cell epitope presented by HLA-A24 molecule in hepatitis C virus infection. J Hepatol 34:930–935 [CrossRef]
    [Google Scholar]
  20. Lalvani A., Brookes R., Hambleton S., Britton W. J., Hill A. V., McMichael A. J. 1997; Rapid effector function in CD8+ memory T cells. J Exp Med 186:859–865 [CrossRef]
    [Google Scholar]
  21. Lauer G. M., Ouchi K., Chung R. T. 8 other authors 2002; Comprehensive analysis of CD8+-T-cell responses against hepatitis C virus reveals multiple unpredicted specificities. J Virol 76:6104–6113 [CrossRef]
    [Google Scholar]
  22. Lechner F., Wong D. K., Dunbar P. R. 7 other authors 2000; Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191:1499–1512 [CrossRef]
    [Google Scholar]
  23. Löhr H. F., Schmitz D., Arenz M., Weyer S., Gerken G., Meyer zum Buschenfelde K. H. 1999; The viral clearance in interferon-treated chronic hepatitis C is associated with increased cytotoxic T cell frequencies. J Hepatol 31:407–415 [CrossRef]
    [Google Scholar]
  24. Neumann A. U., Lam N. P., Dahari H., Gretch D. R., Wiley T. E., Layden T. J., Perelson A. S. 1998; Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282:103–107 [CrossRef]
    [Google Scholar]
  25. Poynard T., Marcellin P., Lee S. S. 8 other authors 1998; Randomised trial of interferon α 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 352:1426–1432 [CrossRef]
    [Google Scholar]
  26. Rammensee H., Bachmann J., Emmerich N. P., Bachor O. A., Stevanovic S. 1999; syfpeithi: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219 [CrossRef]
    [Google Scholar]
  27. Rehermann B., Chisari F. V. 2000; Cell-mediated immune response to the hepatitis C virus. Curr Top Microbiol Immunol 242:299–325
    [Google Scholar]
  28. Rehermann B., Chang K. M., McHutchison J. G., Kokka R., Houghton M., Chisari F. V. 1996; Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection. J Clin Invest 98:1432–1440 [CrossRef]
    [Google Scholar]
  29. Sobao Y., Tomiyama H., Nakamura S., Sekihara H., Tanaka K., Takiguchi M. 2001; Visual demonstration of hepatitis C virus-specific memory CD8+ T-cell expansion in patients with acute hepatitis C. Hepatology 33:287–294 [CrossRef]
    [Google Scholar]
  30. Thimme R., Oldach D., Chang K. M., Steiger C., Ray S. C., Chisari F. V. 2001; Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 194:1395–1406 [CrossRef]
    [Google Scholar]
  31. Tong M. J., Reddy K. R., Lee W. M. 14 other authors 1997; Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Consensus Interferon Study Group. Hepatology 26:747–754 [CrossRef]
    [Google Scholar]
  32. Vertuani S., Bazzaro M., Gualandi G. 8 other authors 2002; Effect of interferon-alpha therapy on epitope-specific cytotoxic T lymphocyte responses in hepatitis C virus-infected individuals. Eur J Immunol 32:144–154 [CrossRef]
    [Google Scholar]
  33. Ward S., Lauer G., Isba R., Walker B., Klenerman P. 2002; Cellular immune responses against hepatitis C virus: the evidence base 2002. Clin Exp Immunol 128:195–203 [CrossRef]
    [Google Scholar]
  34. Wedemeyer H., He X. S., Nascimbeni M., Davis A. R., Greenberg H. B., Hoofnagle J. H., Liang T. J., Alter H., Rehermann B. 2002; Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 169:3447–3458 [CrossRef]
    [Google Scholar]
  35. Zeuzem S., Feinman S. V., Rasenack J. 9 other authors 2000; Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 343:1666–1672 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.79801-0
Loading
/content/journal/jgv/10.1099/vir.0.79801-0
Loading

Data & Media loading...

Most cited this month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error