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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 Aug 29;355(1400):1085–1092. doi: 10.1098/rstb.2000.0646

Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers.

F Lechner 1, J Sullivan 1, H Spiegel 1, D F Nixon 1, B Ferrari 1, A Davis 1, B Borkowsky 1, H Pollack 1, E Barnes 1, G Dusheiko 1, P Klenerman 1
PMCID: PMC1692808  PMID: 11186310

Abstract

Hepatitis C virus (HCV) infection is a major public health problem, affecting an estimated 3% of the world's population, and over 10% in some countries. Infection in most cases becomes persistent, and can lead to hepatic inflammation, fibrosis and liver failure. The T lymphocyte reponse, in particular that mediated by cytotoxic T lymphocytes (CTLs), is likely to be involved in determining the outcome of infection, although its overall role is not clear. The use of major histocompatibility complex (MHC) class I peptide tetrameric complexes (tetramers) to study antiviral CTL responses has revolutionized our approach to the study of human infection. We have used a panel of MHC class I tetramers to analyse immune responses in HCV-infected individuals at various stages of disease. We find that the CTL response against HCV is vigorous in its early phases but dwindles over time both in terms of lymphocyte number and function. A number of potential explanations for this 'CTL failure' are discussed.

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Selected References

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  1. Altman J. D., Moss P. A., Goulder P. J., Barouch D. H., McHeyzer-Williams M. G., Bell J. I., McMichael A. J., Davis M. M. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996 Oct 4;274(5284):94–96. doi: 10.1126/science.274.5284.94. [DOI] [PubMed] [Google Scholar]
  2. Belles-Isles M., Houde I., Lachance J. G., Noël R., Kingma I., Roy R. Monitoring of cytomegalovirus infections by the CD8+CD38+ T-cell subset in kidney transplant recipients. Transplantation. 1998 Jan 27;65(2):279–282. doi: 10.1097/00007890-199801270-00026. [DOI] [PubMed] [Google Scholar]
  3. Borysiewicz L. K., Graham S., Hickling J. K., Mason P. D., Sissons J. G. Human cytomegalovirus-specific cytotoxic T cells: their precursor frequency and stage specificity. Eur J Immunol. 1988 Feb;18(2):269–275. doi: 10.1002/eji.1830180214. [DOI] [PubMed] [Google Scholar]
  4. Callan M. F., Steven N., Krausa P., Wilson J. D., Moss P. A., Gillespie G. M., Bell J. I., Rickinson A. B., McMichael A. J. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat Med. 1996 Aug;2(8):906–911. doi: 10.1038/nm0896-906. [DOI] [PubMed] [Google Scholar]
  5. Callan M. F., Tan L., Annels N., Ogg G. S., Wilson J. D., O'Callaghan C. A., Steven N., McMichael A. J., Rickinson A. B. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med. 1998 May 4;187(9):1395–1402. doi: 10.1084/jem.187.9.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carmichael A., Jin X., Sissons P., Borysiewicz L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J Exp Med. 1993 Feb 1;177(2):249–256. doi: 10.1084/jem.177.2.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cerny A., McHutchison J. G., Pasquinelli C., Brown M. E., Brothers M. A., Grabscheid B., Fowler P., Houghton M., Chisari F. V. Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif. J Clin Invest. 1995 Feb;95(2):521–530. doi: 10.1172/JCI117694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chang K. M., Rehermann B., McHutchison J. G., Pasquinelli C., Southwood S., Sette A., Chisari F. V. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J Clin Invest. 1997 Nov 1;100(9):2376–2385. doi: 10.1172/JCI119778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen J. The scientific challenge of hepatitis C. Science. 1999 Jul 2;285(5424):26–30. doi: 10.1126/science.285.5424.26. [DOI] [PubMed] [Google Scholar]
  10. Cooper S., Erickson A. L., Adams E. J., Kansopon J., Weiner A. J., Chien D. Y., Houghton M., Parham P., Walker C. M. Analysis of a successful immune response against hepatitis C virus. Immunity. 1999 Apr;10(4):439–449. doi: 10.1016/s1074-7613(00)80044-8. [DOI] [PubMed] [Google Scholar]
  11. Diepolder H. M., Zachoval R., Hoffmann R. M., Wierenga E. A., Santantonio T., Jung M. C., Eichenlaub D., Pape G. R. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet. 1995 Oct 14;346(8981):1006–1007. doi: 10.1016/s0140-6736(95)91691-1. [DOI] [PubMed] [Google Scholar]
  12. Dunbar P. R., Ogg G. S., Chen J., Rust N., van der Bruggen P., Cerundolo V. Direct isolation, phenotyping and cloning of low-frequency antigen-specific cytotoxic T lymphocytes from peripheral blood. Curr Biol. 1998 Mar 26;8(7):413–416. doi: 10.1016/s0960-9822(98)70161-7. [DOI] [PubMed] [Google Scholar]
  13. Gerlach J. T., Diepolder H. M., Jung M. C., Gruener N. H., Schraut W. W., Zachoval R., Hoffmann R., Schirren C. A., Santantonio T., Pape G. R. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology. 1999 Oct;117(4):933–941. doi: 10.1016/s0016-5085(99)70353-7. [DOI] [PubMed] [Google Scholar]
  14. Giorgi J. V., Liu Z., Hultin L. E., Cumberland W. G., Hennessey K., Detels R. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1993 Aug;6(8):904–912. [PubMed] [Google Scholar]
  15. Giuggio V. M., Bonkovsky H. L., Smith J., Rothman A. L. Inefficient recognition of autologous viral sequences by intrahepatic hepatitis C virus-specific cytotoxic T lymphocytes in chronically infected subjects. Virology. 1998 Nov 10;251(1):132–140. doi: 10.1006/viro.1998.9401. [DOI] [PubMed] [Google Scholar]
  16. He X. S., Rehermann B., López-Labrador F. X., Boisvert J., Cheung R., Mumm J., Wedemeyer H., Berenguer M., Wright T. L., Davis M. M. 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. 1999 May 11;96(10):5692–5697. doi: 10.1073/pnas.96.10.5692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heintges T., Wands J. R. Hepatitis C virus: epidemiology and transmission. Hepatology. 1997 Sep;26(3):521–526. doi: 10.1002/hep.510260338. [DOI] [PubMed] [Google Scholar]
  18. Ho H. N., Hultin L. E., Mitsuyasu R. T., Matud J. L., Hausner M. A., Bockstoce D., Chou C. C., O'Rourke S., Taylor J. M., Giorgi J. V. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol. 1993 Apr 1;150(7):3070–3079. [PubMed] [Google Scholar]
  19. Kaufmann G. R., Zaunders J. J., Cunningham P., Cooper D. A. Phenotypic analysis of CD8+ T lymphocytes in a cohort of HIV type 1-infected patients treated with saquinavir, ritonavir, and two nucleoside analogs for 1 year, and association with plasma HIV type 1 RNA. AIDS Res Hum Retroviruses. 1999 Jul 20;15(11):963–972. doi: 10.1089/088922299310476. [DOI] [PubMed] [Google Scholar]
  20. Klenerman P., Zinkernagel R. M. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature. 1998 Jul 30;394(6692):482–485. doi: 10.1038/28860. [DOI] [PubMed] [Google Scholar]
  21. Koup R. A., Safrit J. T., Cao Y., Andrews C. A., McLeod G., Borkowsky W., Farthing C., Ho D. D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994 Jul;68(7):4650–4655. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koziel M. J., Dudley D., Afdhal N., Grakoui A., Rice C. M., Choo Q. L., Houghton M., Walker B. D. HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release. J Clin Invest. 1995 Nov;96(5):2311–2321. doi: 10.1172/JCI118287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lechner F., Wong D. K., Dunbar P. R., Chapman R., Chung R. T., Dohrenwend P., Robbins G., Phillips R., Klenerman P., Walker B. D. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med. 2000 May 1;191(9):1499–1512. doi: 10.1084/jem.191.9.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Minutello M. A., Pileri P., Unutmaz D., Censini S., Kuo G., Houghton M., Brunetto M. R., Bonino F., Abrignani S. Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. J Exp Med. 1993 Jul 1;178(1):17–25. doi: 10.1084/jem.178.1.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Missale G., Bertoni R., Lamonaca V., Valli A., Massari M., Mori C., Rumi M. G., Houghton M., Fiaccadori F., Ferrari C. Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Invest. 1996 Aug 1;98(3):706–714. doi: 10.1172/JCI118842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nelson D. R., Marousis C. G., Ohno T., Davis G. L., Lau J. Y. Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C. Hepatology. 1998 Jul;28(1):225–230. doi: 10.1002/hep.510280129. [DOI] [PubMed] [Google Scholar]
  27. Neumann A. U., Lam N. P., Dahari H., Gretch D. R., Wiley T. E., Layden T. J., Perelson A. S. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998 Oct 2;282(5386):103–107. doi: 10.1126/science.282.5386.103. [DOI] [PubMed] [Google Scholar]
  28. Ogg G. S., Jin X., Bonhoeffer S., Dunbar P. R., Nowak M. A., Monard S., Segal J. P., Cao Y., Rowland-Jones S. L., Cerundolo V. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science. 1998 Mar 27;279(5359):2103–2106. doi: 10.1126/science.279.5359.2103. [DOI] [PubMed] [Google Scholar]
  29. Planz O., Ehl S., Furrer E., Horvath E., Bründler M. A., Hengartner H., Zinkernagel R. M. A critical role for neutralizing-antibody-producing B cells, CD4(+) T cells, and interferons in persistent and acute infections of mice with lymphocytic choriomeningitis virus: implications for adoptive immunotherapy of virus carriers. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6874–6879. doi: 10.1073/pnas.94.13.6874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rehermann B., Chang K. M., McHutchinson J., Kokka R., Houghton M., Rice C. M., Chisari F. V. Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients. J Virol. 1996 Oct;70(10):7092–7102. doi: 10.1128/jvi.70.10.7092-7102.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rehermann B., Chang K. M., McHutchison J. G., Kokka R., Houghton M., Chisari F. V. Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection. J Clin Invest. 1996 Sep 15;98(6):1432–1440. doi: 10.1172/JCI118931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reid S. W., McAdam S., Smith K. J., Klenerman P., O'Callaghan C. A., Harlos K., Jakobsen B. K., McMichael A. J., Bell J. I., Stuart D. I. Antagonist HIV-1 Gag peptides induce structural changes in HLA B8. J Exp Med. 1996 Dec 1;184(6):2279–2286. doi: 10.1084/jem.184.6.2279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Thomsen A. R., Johansen J., Marker O., Christensen J. P. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice. J Immunol. 1996 Oct 1;157(7):3074–3080. [PubMed] [Google Scholar]
  34. Valiante N. M., D'Andrea A., Crotta S., Lechner F., Klenerman P., Nuti S., Wack A., Abrignani S. Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C. Immunol Rev. 2000 Apr;174:77–89. doi: 10.1034/j.1600-0528.2002.017417.x. [DOI] [PubMed] [Google Scholar]
  35. Weiner A., Erickson A. L., Kansopon J., Crawford K., Muchmore E., Hughes A. L., Houghton M., Walker C. M. Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2755–2759. doi: 10.1073/pnas.92.7.2755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wong D. K., Dudley D. D., Afdhal N. H., Dienstag J., Rice C. M., Wang L., Houghton M., Walker B. D., Koziel M. J. Liver-derived CTL in hepatitis C virus infection: breadth and specificity of responses in a cohort of persons with chronic infection. J Immunol. 1998 Feb 1;160(3):1479–1488. [PubMed] [Google Scholar]
  37. Zinkernagel R. M., Haenseler E., Leist T., Cerny A., Hengartner H., Althage A. T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay? J Exp Med. 1986 Oct 1;164(4):1075–1092. doi: 10.1084/jem.164.4.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zinkernagel R. M. Immunology taught by viruses. Science. 1996 Jan 12;271(5246):173–178. doi: 10.1126/science.271.5246.173. [DOI] [PubMed] [Google Scholar]

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