1887

Abstract

(HBV) is a major cause of chronic liver inflammation worldwide. Recent knowledge of the virological and immunological events secondary to HBV infection has increased our understanding of the mechanisms involved in viral clearance and persistence. In this review, how the early virological and immunological events might influence the development of a coordinate activation of adaptive immunity necessary to control HBV infection is analysed. The mechanism(s) by which high levels of viral antigens, liver immunological features, regulatory cells and dendritic cell defects might maintain the HBV-specific immunological collapse, typical of chronic hepatitis B patients, is also examined.

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2006-06-01
2019-10-20
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References

  1. Accapezzato, D., Francavilla, V., Paroli, M., Casciaro, M., Chircu, L. V., Cividini, A., Abrignani, S., Mondelli, M. U. & Barnaba, V. ( 2004; ). Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection. J Clin Invest 113, 963–972.[CrossRef]
    [Google Scholar]
  2. Alberti, A., Diana, S., Sculard, G. H., Eddleston, A. L. & Williams, R. ( 1978; ). Detection of a new antibody system reacting with Dane particles in hepatitis B virus infection. Br Med J 2, 1056–1058.[CrossRef]
    [Google Scholar]
  3. Alberti, A., Chemello, L. & Benvegnu, L. ( 1999; ). Natural history of hepatitis C. J Hepatol 31, S17–S24.[CrossRef]
    [Google Scholar]
  4. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. ( 2001; ). Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738.[CrossRef]
    [Google Scholar]
  5. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B. & Palucka, K. ( 2000; ). Immunobiology of dendritic cells. Annu Rev Immunol 18, 767–811.[CrossRef]
    [Google Scholar]
  6. Baron, J. L., Gardiner, L., Nishimura, S., Shinkai, K., Locksley, R. & Ganem, D. ( 2002; ). Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 16, 583–594.[CrossRef]
    [Google Scholar]
  7. Beckebaum, S., Cicinnati, V. R., Dworacki, G. & 8 other authors ( 2002; ). Reduction in the circulating pDC1/pDC2 ratio and impaired function of ex vivo-generated DC1 in chronic hepatitis B infection. Clin Immunol 104, 138–150.[CrossRef]
    [Google Scholar]
  8. Berquist, K. R., Peterson, J. M., Murphy, B. L., Ebert, J. W., Maynard, J. E. & Purcell, R. H. ( 1975; ). Hepatitis B antigens in serum and liver of chimpanzees acutely infected with hepatitis B virus. Infect Immun 12, 602–605.
    [Google Scholar]
  9. Bertoletti, A. & Ferrari, C. ( 2003; ). Kinetics of the immune response during HBV and HCV infection. Hepatology 38, 4–13.
    [Google Scholar]
  10. Bertoletti, A., Ferrari, C., Fiaccadori, F., Penna, A., Margolskee, R., Schlicht, H. J., Fowler, P., Guilhot, S. & Chisari, F. V. ( 1991; ). HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci U S A 88, 10445–10449.[CrossRef]
    [Google Scholar]
  11. Bertoletti, A., Costanzo, A., Chisari, F. V. & 7 other authors ( 1994; ). Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope. J Exp Med 180, 933–943.[CrossRef]
    [Google Scholar]
  12. Bertoletti, A., Southwood, S., Chesnut, R. & 7 other authors ( 1997; ). Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18-27: interaction with HLA and T-cell receptor. Hepatology 26, 1027–1034.[CrossRef]
    [Google Scholar]
  13. Bertolino, P., Trescol-Biemont, M. C. & Rabourdin-Combe, C. ( 1998; ). Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. Eur J Immunol 28, 221–236.[CrossRef]
    [Google Scholar]
  14. Bertolino, P., Bowen, D. G., McCaughan, G. W. & Fazekas de St Groth, B. ( 2001; ). Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol 166, 5430–5438.[CrossRef]
    [Google Scholar]
  15. Bertoni, R., Sidney, J., Fowler, P., Chesnut, R. W., Chisari, F. V. & Sette, A. ( 1997; ). Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Invest 100, 503–513.[CrossRef]
    [Google Scholar]
  16. Bigger, C. B., Brasky, K. M. & Lanford, R. E. ( 2001; ). DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 75, 7059–7066.[CrossRef]
    [Google Scholar]
  17. Biron, C. A. ( 2001; ). Interferons alpha and beta as immune regulators – a new look. Immunity 14, 661–664.[CrossRef]
    [Google Scholar]
  18. Bocharov, G., Ludewig, B., Bertoletti, A., Klenerman, P., Junt, T., Krebs, P., Luzyanina, T., Fraser, C. & Anderson, R. M. ( 2004; ). Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses. J Virol 78, 2247–2254.[CrossRef]
    [Google Scholar]
  19. Bocher, W. O., Herzog-Hauff, S., Schlaak, J., Meyer zum Buschenfeld, K. H. & Lohr, H. F. ( 1999; ). Kinetics of hepatitis B surface antigen-specific immune responses in acute and chronic hepatitis B or after HBs vaccination: stimulation of the in vitro antibody response by interferon gamma. Hepatology 29, 238–244.[CrossRef]
    [Google Scholar]
  20. Boni, C., Penna, A., Ogg, G. S. & 9 other authors ( 2001; ). Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 33, 963–971.[CrossRef]
    [Google Scholar]
  21. Boni, C., Penna, A., Bertoletti, A. & 10 other authors ( 2003; ). Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J Hepatol 39, 595–605.[CrossRef]
    [Google Scholar]
  22. Bowen, D. G., Zen, M., Holz, L., Davis, T., McCaughan, G. W. & Bertolino, P. ( 2004; ). The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 114, 701–712.[CrossRef]
    [Google Scholar]
  23. Brunetto, M. R., Giarin, M. M., Oliveri, F. & 8 other authors ( 1991; ). Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A 88, 4186–4190.[CrossRef]
    [Google Scholar]
  24. Celis, E., Ou, D. & Otvos, L., Jr ( 1988; ). Recognition of hepatitis B surface antigen by human T lymphocytes. Proliferative and cytotoxic responses to a major antigenic determinant defined by synthetic peptides. J Immunol 140, 1808–1815.
    [Google Scholar]
  25. Chang, J. J., Wightman, F., Bartholomeusz, A., Ayres, A., Kent, S. J., Sasadeusz, J. & Lewin, S. R. ( 2005; ). Reduced hepatitis B virus (HBV)-specific CD4+ T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy. J Virol 79, 3038–3051.[CrossRef]
    [Google Scholar]
  26. Chen, M. T., Billaud, J. N., Sallberg, M., Guidotti, L. G., Chisari, F. V., Jones, J., Hughes, J. & Milich, D. R. ( 2004; ). A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci U S A 101, 14913–14918.[CrossRef]
    [Google Scholar]
  27. Chen, M., Sallberg, M., Hughes, J., Jones, J., Guidotti, L. G., Chisari, F. V., Billaud, J. N. & Milich, D. R. ( 2005; ). Immune tolerance split between hepatitis B virus precore and core proteins. J Virol 79, 3016–3027.[CrossRef]
    [Google Scholar]
  28. Chisari, F. V. & Ferrari, C. ( 1995; ). Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13, 29–60.[CrossRef]
    [Google Scholar]
  29. Ciurea, A., Hunziker, L., Klenerman, P., Hengartner, H. & Zinkernagel, R. M. ( 2001; ). Impairment of CD4+ T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants. J Exp Med 193, 297–305.[CrossRef]
    [Google Scholar]
  30. Coffin, C. S. & Michalak, T. I. ( 1999; ). Persistence of infectious hepadnavirus in the offspring of woodchuck mothers recovered from viral hepatitis. J Clin Invest 104, 203–212.[CrossRef]
    [Google Scholar]
  31. Cote, P. J., Toshkov, I., Bellezza, C. & 9 other authors ( 2000; ). Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection: increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection. Hepatology 32, 807–817.[CrossRef]
    [Google Scholar]
  32. Crispe, I. N., Dao, T., Klugewitz, K., Mehal, W. Z. & Metz, D. P. ( 2000; ). The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 174, 47–62.[CrossRef]
    [Google Scholar]
  33. Ferrari, C., Penna, A., Bertoletti, A., Cavalli, A., Valli, A., Schianchi, C. & Fiaccadori, F. ( 1989; ). The preS1 antigen of hepatitis B virus is highly immunogenic at the T cell level in man. J Clin Invest 84, 1314–1319.[CrossRef]
    [Google Scholar]
  34. Ferrari, C., Penna, A., Bertoletti, A., Valli, A., Antoni, A. D., Giuberti, T., Cavalli, A., Petit, M. A. & Fiaccadori, F. ( 1990; ). Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. J Immunol 145, 3442–3449.
    [Google Scholar]
  35. Ferrari, C., Bertoletti, A., Penna, A. & 8 other authors ( 1991; ). Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen. J Clin Invest 88, 214–222.[CrossRef]
    [Google Scholar]
  36. Fong, T. L., Di Bisceglie, A. M., Biswas, R., Waggoner, J. G., Wilson, L., Claggett, J. & Hoofnagle, J. H. ( 1994; ). High levels of viral replication during acute hepatitis B infection predict progression to chronicity. J Med Virol 43, 155–158.[CrossRef]
    [Google Scholar]
  37. Franzese, O., Kennedy, P. T., Gehring, A. J., Gotto, J., Williams, R., Maini, M. K. & Bertoletti, A. ( 2005; ). Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J Virol 79, 3322–3328.[CrossRef]
    [Google Scholar]
  38. Gallimore, A., Dumrese, T., Hengartner, H., Zinkernagel, R. M. & Rammensee, H. G. ( 1998; ). Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides. J Exp Med 187, 1647–1657.[CrossRef]
    [Google Scholar]
  39. Ganem, D. & Prince, A. M. ( 2004; ). Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 350, 1118–1129.[CrossRef]
    [Google Scholar]
  40. Grady, G. F., Lee, V. A., Prince, A. M. & 14 other authors ( 1978; ). Hepatitis B immune globulin for accidental exposures among medical personnel: final report of a multicenter controlled trial. J Infect Dis 138, 625–638.[CrossRef]
    [Google Scholar]
  41. Guidotti, L. G. & Chisari, F. V. ( 1996; ). To kill or to cure: options in host defense against viral infection. Curr Opin Immunol 8, 478–483.[CrossRef]
    [Google Scholar]
  42. Guidotti, L. G. & Chisari, F. V. ( 2001; ). Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19, 65–91.[CrossRef]
    [Google Scholar]
  43. Guidotti, L. G., Rochford, R., Chung, J., Shapiro, M., Purcell, R. & Chisari, F. V. ( 1999; ). Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829.[CrossRef]
    [Google Scholar]
  44. Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H. & Bauer, S. ( 2004; ). Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529.[CrossRef]
    [Google Scholar]
  45. Hodgson, P. D. & Michalak, T. I. ( 2001; ). Augmented hepatic interferon gamma expression and T-cell influx characterize acute hepatitis progressing to recovery and residual lifelong virus persistence in experimental adult woodchuck hepatitis virus infection. Hepatology 34, 1049–1059.[CrossRef]
    [Google Scholar]
  46. Hwang, Y. K., Kim, N. K., Park, J. M., Lee, K., Han, W. K., Kim, H. I. & Cheong, H. S. ( 2002; ). HLA-A2 1 restricted peptides from the HBx antigen induce specific CTL responses in vitro and in vivo. Vaccine 20, 3770–3777.[CrossRef]
    [Google Scholar]
  47. Hyodo, N., Nakamura, I. & Imawari, M. ( 2004; ). Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection. Clin Exp Immunol 135, 462–466.[CrossRef]
    [Google Scholar]
  48. Isogawa, M., Furuichi, Y. & Chisari, F. V. ( 2005; ). Oscillating CD8+ T cell effector functions after antigen recognition in the liver. Immunity 23, 53–63.[CrossRef]
    [Google Scholar]
  49. Iwarson, S., Wahl, M., Ruttimann, E., Snoy, P., Seto, B. & Gerety, R. J. ( 1988; ). Successful postexposure vaccination against hepatitis B in chimpanzees. J Med Virol 25, 433–439.[CrossRef]
    [Google Scholar]
  50. Jilbert, A. R., Wu, T. T., England, J. M., Hall, P. M., Carp, N. Z., O'Connell, A. P. & Mason, W. S. ( 1992; ). Rapid resolution of duck hepatitis B virus infections occurs after massive hepatocellular involvement. J Virol 66, 1377–1388.
    [Google Scholar]
  51. Jung, M. C., Spengler, U., Schraut, W. & 8 other authors ( 1991; ). Hepatitis B virus antigen-specific T-cell activation in patients with acute and chronic hepatitis B. J Hepatol 13, 310–317.
    [Google Scholar]
  52. Jung, M. C., Hartmann, B., Gerlach, J. T. & 9 other authors ( 1999; ). Virus-specific lymphokine production differs quantitatively but not qualitatively in acute and chronic hepatitis B infection. Virology 261, 165–172.[CrossRef]
    [Google Scholar]
  53. Kafrouni, M. I., Brown, G. R. & Thiele, D. L. ( 2001; ). Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms. J Immunol 167, 1566–1574.[CrossRef]
    [Google Scholar]
  54. Kajino, K., Jilbert, A. R., Saputelli, J., Aldrich, C. E., Cullen, J. & Mason, W. S. ( 1994; ). Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte. J Virol 68, 5792–5803.
    [Google Scholar]
  55. Kakimi, K., Guidotti, L. G., Koezuka, Y. & Chisari, F. V. ( 2000; ). Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192, 921–930.[CrossRef]
    [Google Scholar]
  56. Kakimi, K., Lane, T. E., Chisari, F. V. & Guidotti, L. G. ( 2001; ). Cutting edge: inhibition of hepatitis B virus replication by activated NK T cells does not require inflammatory cell recruitment to the liver. J Immunol 167, 6701–6705.[CrossRef]
    [Google Scholar]
  57. Kakimi, K., Isogawa, M., Chung, J., Sette, A. & Chisari, F. V. ( 2002; ). Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: implications for immunotherapy of persistent viral infections. J Virol 76, 8609–8620.[CrossRef]
    [Google Scholar]
  58. Kalams, S. A. & Walker, B. D. ( 1998; ). The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med 188, 2199–2204.[CrossRef]
    [Google Scholar]
  59. Klein, I. & Crispe, I. N. ( 2006; ). Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J Exp Med 203, 437–447.[CrossRef]
    [Google Scholar]
  60. Korba, B. E., Cote, P. J., Wells, F. V., Baldwin, B., Popper, H., Purcell, R. H., Tennant, B. C. & Gerin, J. L. ( 1989; ). Natural history of woodchuck hepatitis virus infections during the course of experimental viral infection: molecular virologic features of the liver and lymphoid tissues. J Virol 63, 1360–1370.
    [Google Scholar]
  61. Lew, Y. Y. & Michalak, T. I. ( 2001; ). In vitro and in vivo infectivity and pathogenicity of the lymphoid cell-derived woodchuck hepatitis virus. J Virol 75, 1770–1782.[CrossRef]
    [Google Scholar]
  62. Lohr, H. F., Pingel, S., Bocher, W. O., Bernhard, H., Herzog-Hauff, S., Rose-John, S. & Galle, P. R. ( 2002; ). Reduced virus specific T helper cell induction by autologous dendritic cells in patients with chronic hepatitis B – restoration by exogenous interleukin-12. Clin Exp Immunol 130, 107–114.[CrossRef]
    [Google Scholar]
  63. Lok, A. S. & McMahon, B. J. ( 2001; ). Chronic hepatitis B. Hepatology 34, 1225–1241.[CrossRef]
    [Google Scholar]
  64. Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. ( 2003; ). Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198, 513–520.[CrossRef]
    [Google Scholar]
  65. Maini, M. K., Boni, C., Ogg, G. S. & 10 other authors ( 1999; ). Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection. Gastroenterology 117, 1386–1396.[CrossRef]
    [Google Scholar]
  66. Maini, M. K., Boni, C., Lee, C. K. & 12 other authors ( 2000; ). The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 191, 1269–1280.[CrossRef]
    [Google Scholar]
  67. Maloy, K. J. & Powrie, F. ( 2001; ). Regulatory T cells in the control of immune pathology. Nat Immunol 2, 816–822.[CrossRef]
    [Google Scholar]
  68. McClary, H., Koch, R., Chisari, F. V. & Guidotti, L. G. ( 2000; ). Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines. J Virol 74, 2255–2264.[CrossRef]
    [Google Scholar]
  69. Menne, S., Roneker, C. A., Roggendorf, M., Gerin, J. L., Cote, P. J. & Tennant, B. C. ( 2002; ). Deficiencies in the acute-phase cell-mediated immune response to viral antigens are associated with development of chronic woodchuck hepatitis virus infection following neonatal inoculation. J Virol 76, 1769–1780.[CrossRef]
    [Google Scholar]
  70. Milich, D. & Liang, T. J. ( 2003; ). Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38, 1075–1086.[CrossRef]
    [Google Scholar]
  71. Milich, D. R., Jones, J. E., Hughes, J. L., Price, J., Raney, A. K. & McLachlan, A. ( 1990; ). Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci U S A 87, 6599–6603.[CrossRef]
    [Google Scholar]
  72. Milich, D. R., Chen, M. K., Hughes, J. L. & Jones, J. E. ( 1998; ). The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence. J Immunol 160, 2013–2021.
    [Google Scholar]
  73. Missale, G., Redeker, A., Person, J., Fowler, P., Guilhot, S., Schlicht, H. J., Ferrari, C. & Chisari, F. V. ( 1993; ). HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis. J Exp Med 177, 751–762.[CrossRef]
    [Google Scholar]
  74. Mizukoshi, E., Sidney, J., Livingston, B., Ghany, M., Hoofnagle, J. H., Sette, A. & Rehermann, B. ( 2004; ). Cellular immune responses to the hepatitis B virus polymerase. J Immunol 173, 5863–5871.[CrossRef]
    [Google Scholar]
  75. Moretta, L., Bottino, C., Pende, D., Vitale, M., Mingari, M. C. & Moretta, A. ( 2005; ). Human natural killer cells: molecular mechanisms controlling NK cell activation and tumor cell lysis. Immunol Lett 100, 7–13.[CrossRef]
    [Google Scholar]
  76. Nakamura, I., Nupp, J. T., Cowlen, M., Hall, W. C., Tennant, B. C., Casey, J. L., Gerin, J. L. & Cote, P. J. ( 2001; ). Pathogenesis of experimental neonatal woodchuck hepatitis virus infection: chronicity as an outcome of infection is associated with a diminished acute hepatitis that is temporally deficient for the expression of interferon gamma and tumor necrosis factor-alpha messenger RNAs. Hepatology 33, 439–447.[CrossRef]
    [Google Scholar]
  77. Nayersina, R., Fowler, P., Guilhot, S. & 7 other authors ( 1993; ). HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol 150, 4659–4671.
    [Google Scholar]
  78. Ou, R., Zhou, S., Huang, L. & Moskophidis, D. ( 2001; ). Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J Virol 75, 8407–8423.[CrossRef]
    [Google Scholar]
  79. Penna, A., Chisari, F. V., Bertoletti, A., Missale, G., Fowler, P., Giuberti, T., Fiaccadori, F. & Ferrari, C. ( 1991; ). Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen. J Exp Med 174, 1565–1570.[CrossRef]
    [Google Scholar]
  80. Penna, A., Artini, M., Cavalli, A. & 8 other authors ( 1996; ). Long-lasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest 98, 1185–1194.[CrossRef]
    [Google Scholar]
  81. Penna, A., Del Prete, G., Cavalli, A. & 8 other authors ( 1997; ). Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. Hepatology 25, 1022–1027.[CrossRef]
    [Google Scholar]
  82. Rehermann, B., Pasquinelli, C., Mosier, S. M. & Chisari, F. V. ( 1995a; ). Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection. J Clin Invest 96, 1527–1534.[CrossRef]
    [Google Scholar]
  83. Rehermann, B., Fowler, P., Sidney, J., Person, J., Redeker, A., Brown, M., Moss, B., Sette, A. & Chisari, F. V. ( 1995b; ). The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med 181, 1047–1058.[CrossRef]
    [Google Scholar]
  84. Rehermann, B., Ferrari, C., Pasquinelli, C. & Chisari, F. V. ( 1996a; ). The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 2, 1104–1108.[CrossRef]
    [Google Scholar]
  85. Rehermann, B., Lau, D., Hoofnagle, J. H. & Chisari, F. V. ( 1996b; ). Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. J Clin Invest 97, 1655–1665.[CrossRef]
    [Google Scholar]
  86. Reignat, S., Webster, G. J., Brown, D. & 7 other authors ( 2002; ). Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. J Exp Med 195, 1089–1101.[CrossRef]
    [Google Scholar]
  87. Rigopoulou, E. I., Suri, D., Chokshi, S., Mullerova, I., Rice, S., Tedder, R. S., Williams, R. & Naoumov, N. V. ( 2005; ). Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology 42, 1028–1036.[CrossRef]
    [Google Scholar]
  88. Rossol, S., Marinos, G., Carucci, P., Singer, M. V., Williams, R. & Naoumov, N. V. ( 1997; ). Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B. J Clin Invest 99, 3025–3033.[CrossRef]
    [Google Scholar]
  89. Sakaguchi, S. ( 2000; ). Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458.[CrossRef]
    [Google Scholar]
  90. Seeger, C. & Mason, W. S. ( 2000; ). Hepatitis B virus biology. Microbiol Mol Biol Rev 64, 51–68.[CrossRef]
    [Google Scholar]
  91. Sobao, Y., Sugi, K., Tomiyama, H. & 7 other authors ( 2001; ). Identification of hepatitis B virus-specific CTL epitopes presented by HLA-A*2402, the most common HLA class I allele in East Asia. J Hepatol 34, 922–929.[CrossRef]
    [Google Scholar]
  92. Sobao, Y., Tomiyama, H., Sugi, K. & 7 other authors ( 2002; ). The role of hepatitis B virus-specific memory CD8 T cells in the control of viral replication. J Hepatol 36, 105–115.
    [Google Scholar]
  93. Stoop, J. N., van der Molen, R. G., Baan, C. C., van der Laan, L. J., Kuipers, E. J., Kusters, J. G. & Janssen, H. L. ( 2005; ). Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41, 771–778.[CrossRef]
    [Google Scholar]
  94. Su, A. I., Pezacki, J. P., Wodicka, L. & 8 other authors ( 2002; ). Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A 99, 15669–15674.[CrossRef]
    [Google Scholar]
  95. Suvas, S., Kumaraguru, U., Pack, C. D., Lee, S. & Rouse, B. T. ( 2003; ). CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 198, 889–901.[CrossRef]
    [Google Scholar]
  96. Tavakoli, S., Schwerin, W., Rohwer, A. & 9 other authors ( 2004; ). Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection. J Gen Virol 85, 2829–2836.[CrossRef]
    [Google Scholar]
  97. Thimme, R., Chang, K. M., Pemberton, J., Sette, A. & Chisari, F. V. ( 2001; ). Degenerate immunogenicity of an HLA-A2-restricted hepatitis B virus nucleocapsid cytotoxic T-lymphocyte epitope that is also presented by HLA-B51. J Virol 75, 3984–3987.[CrossRef]
    [Google Scholar]
  98. Thimme, R., Bukh, J., Spangenberg, H. C., Wieland, S., Pemberton, J., Steiger, C., Govindarajan, S., Purcell, R. H. & Chisari, F. V. ( 2002; ). Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A 99, 15661–15668.[CrossRef]
    [Google Scholar]
  99. Thimme, R., Wieland, S., Steiger, C., Ghrayeb, J., Reimann, K. A., Purcell, R. H. & Chisari, F. V. ( 2003; ). CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 77, 68–76.[CrossRef]
    [Google Scholar]
  100. Thio, C. L., Thomas, D. L., Karacki, P. & 10 other authors ( 2003; ). Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection. J Virol 77, 12083–12087.[CrossRef]
    [Google Scholar]
  101. Thursz, M. R., Thomas, H. C., Greenwood, B. M. & Hill, A. V. ( 1997; ). Heterozygote advantage for HLA class-II type in hepatitis B virus infection. Nat Genet 17, 11–12.[CrossRef]
    [Google Scholar]
  102. Trobonjaca, Z., Leithauser, F., Moller, P., Schirmbeck, R. & Reimann, J. ( 2001; ). Activating immunity in the liver. I. Liver dendritic cells (but not hepatocytes) are potent activators of IFN-γ release by liver NKT cells. J Immunol 167, 1413–1422.[CrossRef]
    [Google Scholar]
  103. Tsai, S. L., Chen, P. J., Lai, M. Y., Yang, P. M., Sung, J. L., Huang, J. H., Hwang, L. H., Chang, T. H. & Chen, D. S. ( 1992; ). Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest 89, 87–96.[CrossRef]
    [Google Scholar]
  104. Urbani, S., Boni, C., Amadei, B., Fisicaro, P., Cerioni, S., Valli, M. A., Missale, G. & Ferrari, C. ( 2005; ). Acute phase HBV-specific T cell responses associated with HBV persistence after HBV/HCV coinfection. Hepatology 41, 826–831.[CrossRef]
    [Google Scholar]
  105. van der Molen, R. G., Sprengers, D., Binda, R. S., de Jong, E. C., Niesters, H. G., Kusters, J. G., Kwekkeboom, J. & Janssen, H. L. ( 2004; ). Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology 40, 738–746.[CrossRef]
    [Google Scholar]
  106. Wang, F. S., Xing, L. H., Liu, M. X., Zhu, C. L., Liu, H. G., Wang, H. F. & Lei, Z. Y. ( 2001; ). Dysfunction of peripheral blood dendritic cells from patients with chronic hepatitis B virus infection. World J Gastroenterol 7, 537–541.
    [Google Scholar]
  107. Webster, G. J., Reignat, S., Maini, M. K. & 9 other authors ( 2000; ). Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 32, 1117–1124.[CrossRef]
    [Google Scholar]
  108. Webster, G. J., Reignat, S., Brown, D., Ogg, G. S., Jones, L., Seneviratne, S. L., Williams, R., Dusheiko, G. & Bertoletti, A. ( 2004; ). Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J Virol 78, 5707–5719.[CrossRef]
    [Google Scholar]
  109. Whalley, S. A., Murray, J. M., Brown, D., Webster, G. J., Emery, V. C., Dusheiko, G. M. & Perelson, A. S. ( 2001; ). Kinetics of acute hepatitis B virus infection in humans. J Exp Med 193, 847–854.[CrossRef]
    [Google Scholar]
  110. Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R. & Ahmed, R. ( 2003; ). Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77, 4911–4927.[CrossRef]
    [Google Scholar]
  111. Wieland, S. F. & Chisari, F. V. ( 2005; ). Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 79, 9369–9380.[CrossRef]
    [Google Scholar]
  112. Wieland, S. F., Guidotti, L. G. & Chisari, F. V. ( 2000; ). Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol 74, 4165–4173.[CrossRef]
    [Google Scholar]
  113. Wieland, S., Thimme, R., Purcell, R. H. & Chisari, F. V. ( 2004; ). Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 101, 6669–6674.[CrossRef]
    [Google Scholar]
  114. Zhou, S., Ou, R., Huang, L., Price, G. E. & Moskophidis, D. ( 2004; ). Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses during chronic viral infection. J Virol 78, 3578–3600.[CrossRef]
    [Google Scholar]
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