1887

Abstract

This paper investigates the role of CTL and antibody responses in hepatitis C virus (HCV) dynamics and pathology. Mathematical models suggest that a strong CTL response is required for resolution of HCV infection and that a weak CTL response can result in persistent infection. According to the model, establishment of persistent infection is accompanied mainly by an ongoing antibody response, while CTLs are not maintained at high levels. In the model, this outcome correlates with absence of pathology. Persistent infection in the face of an ongoing antibody response can result in evolution of antigenic escape. According to the model, evolution towards escape from antibodies can shift the balance of immune responses so that the weak CTL levels become increasingly more dominant relative to antibodies. This shift results in onset of liver pathology as the virus evolves towards increased levels of antigenic escape. Therefore, the relative balance of the immune response can be a decisive factor that determines whether patients are asymptomatic or whether pathology is observed. Virus evolution can shift this balance towards pathology over time. Theoretical results are discussed in the context of published data.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.19118-0
2003-07-01
2019-12-06
Loading full text...

Full text loading...

/deliver/fulltext/jgv/84/7/vir841743.html?itemId=/content/journal/jgv/10.1099/vir.0.19118-0&mimeType=html&fmt=ahah

References

  1. Arnaout, R. A. & Nowak, M. A. ( 2000; ). Competitive coexistence in antiviral immunity. J Theor Biol 204, 431–441.[CrossRef]
    [Google Scholar]
  2. Borghans, J. A., Taams, L. S., Wauben, M. H. & de Boer, R. J. ( 1999; ). Competition for antigenic sites during T cell proliferation: a mathematical interpretation of in vitro data. Proc Natl Acad Sci U S A 96, 10782–10787.[CrossRef]
    [Google Scholar]
  3. Cabot, B., Martell, M., Esteban, J. I., Sauleda, S., Otero, T., Esteban, R., Guardia, J. & Gomez, J. ( 2000; ). Nucleotide and amino acid complexity of hepatitis C virus quasispecies in serum and liver. J Virol 74, 805–811.[CrossRef]
    [Google Scholar]
  4. Chang, K. M., Rehermann, B. & Chisari, F. V. ( 1997; ). Immunopathology of hepatitis C. Springer Semin Immunopathol 19, 57–68.[CrossRef]
    [Google Scholar]
  5. Chang, K. M., Thimme, R., Melpolder, J. J., Oldach, D., Pemberton, J., Moorhead-Loudis, J., McHutchison, J. G., Alter, H. J. & Chisari, F. V. ( 2001; ). Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection. Hepatology 33, 267–276.[CrossRef]
    [Google Scholar]
  6. Cooper, S., Erickson, A. L., Adams, E. J., Kansopon, J., Weiner, A. J., Chien, D. Y., Houghton, M., Parham, P. & Walker, C. M. ( 1999; ). Analysis of a successful immune response against hepatitis C virus. Immunity 10, 439–449.[CrossRef]
    [Google Scholar]
  7. Curran, R., Jameson, C. L., Craggs, J. K., Grabowska, A. M., Thomson, B. J., Robins, A., Irving, W. L. & Ball, J. K. ( 2002; ). Evolutionary trends of the first hypervariable region of the hepatitis C virus E2 protein in individuals with differing liver disease severity. J Gen Virol 83, 11–23.
    [Google Scholar]
  8. de Araujo, E. S., Cavalheiro Nde, P., Cubero Leitao, R. M., Borges Tosta, R. A. & Barone, A. A. ( 2002; ). Hepatitis C viral load does not predict disease outcome: going beyond numbers. Rev Inst Med Trop Sao Paulo 44, 71–78.
    [Google Scholar]
  9. Einav, S. & Koziel, M. J. ( 2002; ). Immunopathogenesis of hepatitis C virus in the immunosuppressed host. Transpl Infect Dis 4, 85–92.[CrossRef]
    [Google Scholar]
  10. Farci, P. ( 2001; ). Hepatitis C virus. The importance of viral heterogeneity. Clin Liver Dis 5, 895–916.[CrossRef]
    [Google Scholar]
  11. Farci, P., Shimoda, A., Coiana, A. & 9 other authors ( 2000; ). The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 288, 339–344.[CrossRef]
    [Google Scholar]
  12. Forns, X., Purcell, R. H. & Bukh, J. ( 1999; ). Quasispecies in viral persistence and pathogenesis of hepatitis C virus. Trends Microbiol 7, 402–410.[CrossRef]
    [Google Scholar]
  13. Freitas, A. A. & Rocha, B. ( 2000; ). Population biology of lymphocytes: the flight for survival. Annu Rev Immunol 18, 83–111.[CrossRef]
    [Google Scholar]
  14. Hoofnagle, J. H. ( 1999; ). Management of hepatitis C: current and future perspectives. J Hepatol 31, 264–268.[CrossRef]
    [Google Scholar]
  15. Klenerman, P., Lechner, F., Kantzanou, M., Ciurea, A., Hengartner, H. & Zinkernagel, R. ( 2000; ). Viral escape and the failure of cellular immune responses. Science 289, 2003.[CrossRef]
    [Google Scholar]
  16. Layden, T. J., Lam, N. P. & Wiley, T. E. ( 1999; ). Hepatitis C viral dynamics. Clin Liver Dis 3, 793–810.[CrossRef]
    [Google Scholar]
  17. Layden, T. J., Mika, B. & Wiley, T. E. ( 2000; ). Hepatitis C kinetics: mathematical modeling of viral response to therapy. Semin Liver Dis 20, 173–183.[CrossRef]
    [Google Scholar]
  18. Lechner, F., Gruener, N. H., Urbani, S. & 8 other authors ( 2000a; ). CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur J Immunol 30, 2479–2487.[CrossRef]
    [Google Scholar]
  19. Lechner, F., Sullivan, J., Spiegel, H. & 8 other authors ( 2000b; ). Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers. Philos Trans R Soc Lond Ser B Biol Sci 355, 1085–1092.[CrossRef]
    [Google Scholar]
  20. Lechner, F., Wong, D. K., Dunbar, P. R. & 7 other authors ( 2000c; ). Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191, 1499–1512.[CrossRef]
    [Google Scholar]
  21. Lyra, A. C., Fan, X., Lang, D. M., Yusim, K., Ramrakhiani, S., Brunt, E. M., Korber, B., Perelson, A. S. & Di Bisceglie, A. M. ( 2002; ). Evolution of hepatitis C viral quasispecies after liver transplantation. Gastroenterology 123, 1485–1493.[CrossRef]
    [Google Scholar]
  22. Major, M. E., Mihalik, K., Fernandez, J., Seidman, J., Kleiner, D., Kolykhalov, A. A., Rice, C. M. & Feinstone, S. M. ( 1999; ). Long-term follow-up of chimpanzees inoculated with the first infectious clone for hepatitis C virus. J Virol 73, 3317–3325.
    [Google Scholar]
  23. Manzin, A., Solforosi, L., Giostra, F. & 7 other authors ( 1997; ). Quantitative analysis of hepatitis C virus activity in vivo in different groups of untreated patients. Arch Virol 142, 465–472.[CrossRef]
    [Google Scholar]
  24. McCaughan, G. W. & Zekry, A. ( 2000; ). Effects of immunosuppression and organ transplantation on the natural history and immunopathogenesis of hepatitis C virus infection. Transpl Infect Dis 2, 166–185.[CrossRef]
    [Google Scholar]
  25. 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-α therapy. Science 282, 103–107.[CrossRef]
    [Google Scholar]
  26. Nowak, M. A., Anderson, R. M., McLean, A. R., Wolfs, T. F. W., Goudsmit, J. & May, R. M. ( 1991; ). Antigenic diversity thresholds and the development of AIDS. Science 254, 963–969.[CrossRef]
    [Google Scholar]
  27. Pontisso, P., Bellati, G., Brunetto, M. & 9 other authors ( 1999; ). Hepatitis C virus RNA profiles in chronically infected individuals: do they relate to disease activity? Hepatology 29, 585–589.[CrossRef]
    [Google Scholar]
  28. Puoti, C., Stati, T. & Magrini, A. ( 1999; ). Serum HCV RNA titer does not predict the severity of liver damage in HCV carriers with normal aminotransferase levels. Liver 19, 104–109.[CrossRef]
    [Google Scholar]
  29. Regoes, R. R., Wodarz, D. & Nowak, M. A. ( 1998; ). Virus dynamics: the effect of target cell limitation and immune responses on virus evolution. J Theor Biol 191, 451–462.[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. Thomson, M., Nascimbeni, M., Gonzales, S., Murthy, K. K., Rehermann, B. & Liang, T. J. ( 2001; ). Emergence of a distinct pattern of viral mutations in chimpanzees infected with a homogeneous inoculum of hepatitis C virus. Gastroenterology 121, 1226–1233.[CrossRef]
    [Google Scholar]
  32. Weiner, A. J., Geysen, H. M., Christopherson, C. & 12 other authors ( 1992; ). 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 89, 3468–3472.[CrossRef]
    [Google Scholar]
  33. Wodarz, D. & Nowak, M. A. ( 2000; ). CD8 memory, immunodominance, and antigenic escape. Eur J Immunol 30, 2704–2712.[CrossRef]
    [Google Scholar]
  34. Wodarz, D., Christensen, J. P. & Thomsen, A. R. ( 2002; ). The importance of lytic and nonlytic immune responses in viral infections. Trends Immunol 23, 194–200.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.19118-0
Loading
/content/journal/jgv/10.1099/vir.0.19118-0
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