Skip to main content

Advertisement

Log in

Immunity and persistence in hepatitis C virus infection

  • Published:
Current Hepatitis Reports Aims and scope Submit manuscript

Abstract

Humans are the only known natural host for the hepatitis C virus and the majority of cases result in chronic infection. Identification of acute infection is difficult because symptoms are often subtle or absent. Thus, much remains to be learned about the early mechanisms conferring resolution of infection. The study of spontaneously resolved individuals has revealed a multispecific and sustained antigen-specific immune response, including CD4+ and CD8+ T cells. Evidence is mounting that a cooperative immune response involving both innate and adaptive immunity may be required to successfully eradicate hepatitis C virus infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium [no authors listed]. J Viral Hepat 1999, 6:35–47.

  2. Mizukoshi E, Rehermann B: Immune responses and immunity in hepatitis C virus infection. J Gastroenterol 2001, 36:799–808.

    Article  PubMed  CAS  Google Scholar 

  3. Bartenschlager R, Lohmann V: Replication of hepatitis C virus. J Gen Virol 2000, 81:1631–1648.

    PubMed  CAS  Google Scholar 

  4. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH: Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 2000, 132:296–305.

    PubMed  CAS  Google Scholar 

  5. Reed KE, Rice CM: Molecular characterization of hepatitis C virus. In Hepatitis C Virus, edn 2. Edited by Reesink HW. Basel: Karger; 1998:1–37.

    Google Scholar 

  6. Pawlotsky JM: Hepatitis C virus infection: virus/host interactions. J Viral Hepat 1998, 5(suppl 1):3–8.

    Article  PubMed  Google Scholar 

  7. Marrone A, Sallie R: Genetic heterogeneity of hepatitis C virus: the clinical significance of genotypes and quasispecies behavior. Clin Lab Med 1996, 16:429–449.

    PubMed  CAS  Google Scholar 

  8. Polyak SJ: Hepatitis C virus-cell interactions and their role in pathogenesis. In Clinics in Liver Disease. Edited by Gitlin N. Philidelphia: W.B. Saunders; 2003:67–89. Details recent finding of HCV protein interactions within the host cells.

    Google Scholar 

  9. Yao ZQ, Nguyen DT, Hiotellis AI, Hahn YS: Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway. J Immunol 2001, 167:5264–5272.

    PubMed  CAS  Google Scholar 

  10. Rosen HR, Schwartz JM: Hepatitis C quasispecies and severity of recurrence: cause, consequence or coincidence? Liver Transplant 2002, 8:646–648.

    Article  Google Scholar 

  11. Janeway CA, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197–216.

    Article  PubMed  CAS  Google Scholar 

  12. Cabot B, Martell M, Esteban J, et al.: Longitudinal evaluation of the structure of replicating and circulating hepatitis C virus quasispecies in nonprogressive chronic hepatitis C patients. J Virol 2001, 75:12005–12013.

    Article  PubMed  CAS  Google Scholar 

  13. Crispe IN: Hepatic T cells and liver tolerance. Nat Rev 2003, 3:51–62. Details liver immunology and discusses the role of lymphocytes and infection within the organ.

    Article  CAS  Google Scholar 

  14. Mackay IR: Hepatoimmunology: from horizon to harborside. In Liver Immunology. Philadelphia: Hanley & Belfus; 2003:15–30.

    Google Scholar 

  15. Thimme R, Bukh J, Spangenberg HC, et al.: Viral and immunological determinants of hepatitis C virus clearance, persistence and disease. Proc Natl Acad Sci U S A 2002, 99:15661–15668.

    Article  PubMed  CAS  Google Scholar 

  16. Crotta S, Stilla A, Wack A, et al.: Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med 2002, 195:35–51.

    Article  PubMed  CAS  Google Scholar 

  17. Tseng C, Klimpel GR: Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med 2002, 195:43–49.

    Article  PubMed  CAS  Google Scholar 

  18. Wack A, Soldaini E, Tseng C, et al.: Binding of the hepatitis C virus envelope protein E2 to CD81 provides a co-stimulatory signal for human T cells. Eur J Immunol 2001, 31:166–175.

    Article  PubMed  CAS  Google Scholar 

  19. Deignan T, Curry MP, Doherty DG, et al.: Decrease in hepatic CD56+ T cells and V alpha 24+ natural killer T cells in chronic hepatitis C viral infection. J Hepatol 2002, 37:101–108.

    Article  PubMed  CAS  Google Scholar 

  20. Kawarabayashi N, Seki S, Hatsuse K, et al.: Decrease of CD56+ T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma. Hepatology 2000, 32:962–969.

    Article  PubMed  CAS  Google Scholar 

  21. Leistikow R, Boslaugh T, Ham J, et al.: Direct ex vivo functional analysis of intrahepatic T, NKT and NK cells from HCV-infected and non-infected explants. Poster presented at the American Association for the Study of Liver Diseases. Boston, MA, November 1–5, 2002. Hepatology 2002, 36 [abstract 421].

  22. Golden-Mason L, Rosen H, Asrafel H, et al.: Circulating natural killer (nk) cells are depleted in chronic HCV infection. Talk presented at the Hepatitis C: Past, Present, and Future, International Conference. Dublin, Ireland, June 25–27, 2003.

  23. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998, 392:245–252.

    Article  PubMed  CAS  Google Scholar 

  24. Liu Y-J, Kanzler H, Soumelis V, Gilliet M: Dendritic cell lineage, plasticity, and cross-regulation. Nat Immunol 2001, 2:585–589.

    Article  PubMed  CAS  Google Scholar 

  25. Sousa C, Sher A, Kaye P: The role of dendritic cells in the induction and regulation of immunity to microbial infection. Curr Opin Immunol 1999, 11:392–399.

    Article  Google Scholar 

  26. Wertheimer AM, Miner C, Lewinsohn DM, et al.: Novel CD4+ and CD8+ T cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection. Hepatology 2003, 37:577–589.

    Article  PubMed  CAS  Google Scholar 

  27. Wertheimer AM, Rosen HR: Direct ex-vivo enumeration of human dendritic cell (DC) populations demonstrates HCV infection is associated with loss in both myeloid (mDC) and plasmacytoid (pDC) types. Poster presented at the American Association for the Study of Liver Diseases. Boston, MA, November 1–5, 2002. Hepatology 2002, 36 [abstract 48].

  28. Kanto T, Hayashi N, Takehara T, et al.: Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus infected individuals. J Immunol 1999, 162:5584–5591.

    PubMed  CAS  Google Scholar 

  29. Bain C, Fatmi A, Zoulim F, et al.: Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastoenterology 2001, 120:512–524.

    Article  CAS  Google Scholar 

  30. Auffermann-Gretzinger S, Keeffe EB, Levy S: Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood 2001, 97:3171–3176.

    Article  PubMed  CAS  Google Scholar 

  31. Sarobe P, Lasarte JJ, Casares N, et al.: Abnormal priming of CD4(+) T cells by dendritic cells expressing hepatitis C virus core and E1 proteins. J Virol 2002, 76:5062–5070.

    Article  PubMed  CAS  Google Scholar 

  32. Goutagny N, Fatmi A, De Ledinghen V, et al.: Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. J Infect Dis 2003, 187:1951–1958.

    Article  PubMed  Google Scholar 

  33. Christie JM, Healey CJ, Watson J, et al.: Clinical outcome of hypogammaglobulinemic patients following outbreak of acute hepatitis C: 2 year follow-up. Clin Exp Immunol 1997, 110:4–8.

    Article  PubMed  CAS  Google Scholar 

  34. Mehta SH, Cox A, Hoover DR, et al.: Protection against persistence of hepatitis C. Lancet 2002, 359:1478–1483.

    Article  PubMed  Google Scholar 

  35. Dore GJ, Freeman AJ, Kaldor MJ: Letter to the editor. Lancet 2002, 360:1019–1020.

    Article  PubMed  Google Scholar 

  36. Post JJ, Freeman AJ, Harvey CE, et al.: Immunity against hepatitis C virus infection [letter to the editor]. Lancet 2002, 360:1020; author reply 1020–1021.

    Article  PubMed  Google Scholar 

  37. Stone SF, Lee S, Keane NM, et al.: Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients. J Infect Dis 2002, 186:1498–1502.

    Article  PubMed  CAS  Google Scholar 

  38. Moser M, Murphy KM: Dendritic cell regulation of Th1-Th2 development. Nat Immunol 2001, 1:199–203.

    Article  CAS  Google Scholar 

  39. Nelson DR, Lauwers GY, Lau JYN, Davis GL: Interleukin-10 treatment reduces fibrosis in patients with chronic hepatitis C: A pilot trial in interferon nonresponders. Gastroenterology 2000, 118:655–660.

    Article  PubMed  CAS  Google Scholar 

  40. Missale G, Bertoni R, Lamonaca V, et al.: 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, 98:706–714.

    Article  PubMed  CAS  Google Scholar 

  41. Gerlach JT, Diepolder HM, Jung M-C, et al.: Recurrence of hepatitis C virus after loss of virus-specific CD4+ T-cell response in acute hepatitis C. Gastroenterology 1999, 117:933–941.

    Article  PubMed  CAS  Google Scholar 

  42. Dries V, von Both I, Muller M, et al.: Detection of hepatitis C virus in paraffin-embedded liver biopsies of patients negative for viral RNA in serum. Hepatology 1999, 29:223–229.

    Article  PubMed  CAS  Google Scholar 

  43. Takaki A, Wiese M, Maerten G, et al.: Cellular immune responses persist, humoral responses decrease two decades after recovery from a single source outbreak of hepatitis C. Nat Med 2000, 6:578–582.

    Article  PubMed  CAS  Google Scholar 

  44. Godkin AJ, Thomas HD, Openshaw PJ: Evolution of epitope - specific memory CD4+ T cells after clearance of hepatitis C virus. J Immunol 2002, 169:2210–2214.

    PubMed  CAS  Google Scholar 

  45. Ulsenheimer A, Gerlack T, Guener NH, et al.: Detection of functionally altered hepatitis C Virus specific CD4+ T cells in acute and chronic hepatitis C. Hepatology 2003, 37:1189–1198. A novel analysis that dissects specific phases of T-cell activation during response to HCV antigens.

    Article  PubMed  Google Scholar 

  46. Valitutti S, Muller S, Dessing M, Lanzavecchia A: Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med 1996, 183:1917–1921.

    Article  PubMed  CAS  Google Scholar 

  47. Rosen HR, Miner C, Lewinsohn D, et al.: Frequencies of HCVspecific effector CD4+ T cells by flow cytometry: correlation with clinical disease stages. Hepatology 2002, 35:190–198.

    Article  PubMed  Google Scholar 

  48. Kagi D, Hengartner H: Different roles for cytotoxic T cells in the control of infections with cytopathic versus noncytopathic viruses. Curr Opin Immunol 1996, 8:472–477.

    Article  PubMed  CAS  Google Scholar 

  49. Nelson DR, Marousis CG, Davis GL, et al.: The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C. J Immunol 1997, 158:1473–1481.

    PubMed  CAS  Google Scholar 

  50. Guidotti L, Ishikawa T, Hobbs MV, et al.: Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 1996, 4:25–31.

    Article  PubMed  CAS  Google Scholar 

  51. Frese M, Schwarzle V, Barth K, et al.: Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology 2002, 35:694–703.

    Article  PubMed  CAS  Google Scholar 

  52. Lauer G, Ouchi K, Chung RT, et al.: Comprehensive analysis of CD8+ T cell responses against hepatitis C virus reveals multiple unpredicted specificities. J Virol 2002, 76:6103–6113.

    Google Scholar 

  53. Day CL, Lauer GM, Robbins GK, et al.: Broad specificity of virus-specific CD4+ T-helper-cell in resolved hepatitis C virus infection. J Virol 2002, 76:12584–12595.

    Article  PubMed  CAS  Google Scholar 

  54. Thomson M, Nascimbeni M, Havert MB, et al.: The clearance of hepatitis C virus infection in chimpanzees may not necessarily correlate with the appearance of acquired immunity. J Virol 2003, 77:862–870.

    Article  PubMed  CAS  Google Scholar 

  55. Wedemeyer H, He XS, Nascimbeni M, et al.: Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 2002, 169:3447–3458. Using HLA-A2 tetramers specific for HCV core and NS3 in combination with proliferation, IFN-γ ELISPOT, and cytotoxicity assays, they investigate the frequency and effector function of HCV-specific T cells both directly ex vivo and after short-term culture.

    PubMed  CAS  Google Scholar 

  56. Gruener NH, Lechner F, Jung MC, et al.: Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 2001, 75:5550–5558.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wertheimer, A.M., Rosen, H.R. Immunity and persistence in hepatitis C virus infection. Curr hepatitis rep 2, 152–158 (2003). https://doi.org/10.1007/s11901-003-0017-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-003-0017-y

Keywords

Navigation