Skip to main content

Immunopathogenesis of Chronic Hepatitis B and the Clinical Events That Shape its Natural History

  • Chapter
  • First Online:
Liver Immunology

Abstract

It is estimated that more than two billion people worldwide have been exposed to hepatitis B virus (HBV) and as many as 350 million people have chronic infection [1, 2]. HBV is a major cause of chronic liver disease, liver failure, and hepatocellular carcinoma (HCC). Chronic HBV infection is currently the most common risk factor for HCC worldwide, accounting for more than half of cases and resulting in significant morbidity and mortality [3, 4]. The natural history of HBV infection involves a complex interplay between viral factors and immunologic determinants of spontaneous resolution, chronic infection, and progression of chronic liver disease within the host. In this chapter, we will primarily review the current knowledge about the immunological interface between host response and HBV in addition to the many clinical correlates supporting the assertion that these are critical to viral persistence, disease progression, and response to antiviral therapy.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. World Health Organization. Hepatitis B vaccines: WHO position paper. Wkly Epidemiol Rec. 2009;84:405–20.

    Google Scholar 

  2. Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, Kern ER, et al. National Institutes of Health Consensus Development Conference statement: management of hepatitis B. Ann Intern Med. 2009;150:104–10.

    PubMed  Google Scholar 

  3. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–44.

    PubMed  CAS  Google Scholar 

  4. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    PubMed  Google Scholar 

  5. Tiegs G, Lohse AW. Immune tolerance: what is unique about the liver. J Autoimmun. 2010;34:1–6.

    PubMed  CAS  Google Scholar 

  6. Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009;49:S13–21.

    PubMed  CAS  Google Scholar 

  7. Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol. 1994;68:2026–30.

    PubMed  CAS  Google Scholar 

  8. Benhenda S, Cougot D, Buendia MA, Neuveut C. Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis. Adv Cancer Res. 2009;103:75–109.

    PubMed  CAS  Google Scholar 

  9. Rabe B, Vlachou A, Pante N, Helenius A, Kann M. Nuclear import of hepatitis B virus capsids and release of the viral genome. Proc Natl Acad Sci U S A. 2003;100:9849–54.

    PubMed  CAS  Google Scholar 

  10. Locarnini S. Molecular virology and the development of resistant mutants: implications for therapy. Semin Liver Dis. 2005;25 Suppl 1:9–19.

    PubMed  CAS  Google Scholar 

  11. Wieland SF, Spangenberg HC, Thimme R, Purcell RH, Chisari FV. Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc Natl Acad Sci U S A. 2004;101:2129–34.

    PubMed  CAS  Google Scholar 

  12. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology. 2004;126:1750–8.

    PubMed  CAS  Google Scholar 

  13. Cheng PN, Liu WC, Tsai HW, Wu IC, Chang TT, Young KC. Association of intrahepatic cccDNA reduction with the improvement of liver histology in chronic hepatitis B patients receiving oral antiviral agents. J Med Virol. 2011;83:602–7.

    PubMed  CAS  Google Scholar 

  14. Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC, McDade H. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A. 1996;93:4398–402.

    PubMed  CAS  Google Scholar 

  15. Locarnini S. Molecular virology of hepatitis B virus. Semin Liver Dis. 2004;24 Suppl 1:3–10.

    PubMed  CAS  Google Scholar 

  16. Chotiyaputta W, Lok AS. Hepatitis B virus variants. Nat Rev Gastroenterol Hepatol. 2009;6:453–62.

    PubMed  CAS  Google Scholar 

  17. Webster GJ, Reignat S, Maini MK, Whalley SA, Ogg GS, King A, Brown D, et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology. 2000;32:1117–24.

    PubMed  CAS  Google Scholar 

  18. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77:68–76.

    PubMed  CAS  Google Scholar 

  19. Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science. 1999;284:825–9.

    PubMed  CAS  Google Scholar 

  20. Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH, Chisari FV. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol. 2009;83:9652–62.

    PubMed  CAS  Google Scholar 

  21. Ferrari C, Penna A, Bertoletti A, Valli A, Antoni AD, Giuberti T, Cavalli A, et al. Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. J Immunol. 1990;145:3442–9.

    PubMed  CAS  Google Scholar 

  22. Rehermann B, Fowler P, Sidney J, Person J, Redeker A, Brown M, Moss B, et al. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med. 1995;181:1047–58.

    PubMed  CAS  Google Scholar 

  23. Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology. 1999;117:1386–96.

    PubMed  CAS  Google Scholar 

  24. Yang PL, Althage A, Chung J, Maier H, Wieland S, Isogawa M, Chisari FV. Immune effectors required for hepatitis B virus clearance. Proc Natl Acad Sci U S A. 2010;107:798–802.

    PubMed  CAS  Google Scholar 

  25. Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101:6669–74.

    PubMed  CAS  Google Scholar 

  26. Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996;4:25–36.

    PubMed  CAS  Google Scholar 

  27. Murray JM, Wieland SF, Purcell RH, Chisari FV. Dynamics of hepatitis B virus clearance in chimpanzees. Proc Natl Acad Sci U S A. 2005;102:17780–5.

    PubMed  CAS  Google Scholar 

  28. Phillips S, Chokshi S, Riva A, Evans A, Williams R, Naoumov NV. CD8(+) T cell control of hepatitis B virus replication: direct comparison between cytolytic and noncytolytic functions. J Immunol. 2010;184:287–95.

    PubMed  CAS  Google Scholar 

  29. Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris). 2010;58:258–66.

    CAS  Google Scholar 

  30. Wieland SF, Guidotti LG, Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol. 2000;74:4165–73.

    PubMed  CAS  Google Scholar 

  31. Wieland SF, Eustaquio A, Whitten-Bauer C, Boyd B, Chisari FV. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc Natl Acad Sci U S A. 2005;102:9913–7.

    PubMed  CAS  Google Scholar 

  32. Barker LF, Murray R. Relationship of virus dose to incubation time of clinical hepatitis and time of appearance of hepatitis-associated antigen. Am J Med Sci. 1972;263:27–33.

    PubMed  CAS  Google Scholar 

  33. Chen Z, Cheng Y, Xu Y, Liao J, Zhang X, Hu Y, Zhang Q, et al. Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol. 2008;128:400–8.

    PubMed  CAS  Google Scholar 

  34. Visvanathan K, Skinner NA, Thompson AJ, Riordan SM, Sozzi V, Edwards R, Rodgers S, et al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology. 2007;45:102–10.

    PubMed  CAS  Google Scholar 

  35. Lang T, Lo C, Skinner N, Locarnini S, Visvanathan K, Mansell A. The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. J Hepatol. 2011;55:762–9.

    PubMed  CAS  Google Scholar 

  36. Xu Y, Hu Y, Shi B, Zhang X, Wang J, Zhang Z, Shen F, et al. HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells. Mol Immunol. 2009;46:2640–6.

    PubMed  CAS  Google Scholar 

  37. Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, Zoulim F, et al. Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One. 2011;6:e26315.

    PubMed  CAS  Google Scholar 

  38. Dunn C, Peppa D, Khanna P, Nebbia G, Jones M, Brendish N, Lascar RM, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology. 2009;137:1289–300.

    PubMed  CAS  Google Scholar 

  39. Fisicaro P, Valdatta C, Boni C, Massari M, Mori C, Zerbini A, Orlandini A, et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut. 2009;58:974–82.

    PubMed  CAS  Google Scholar 

  40. Penna A, Chisari FV, Bertoletti A, Missale G, Fowler P, Giuberti T, Fiaccadori F, et al. Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen. J Exp Med. 1991;174:1565–70.

    PubMed  CAS  Google Scholar 

  41. Nayersina R, Fowler P, Guilhot S, Missale G, Cerny A, Schlicht HJ, Vitiello A, et al. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol. 1993;150:4659–71.

    PubMed  CAS  Google Scholar 

  42. Rehermann B, Pasquinelli C, Mosier SM, Chisari FV. Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection. J Clin Invest. 1995;96:1527–34.

    PubMed  CAS  Google Scholar 

  43. Webster GJ, Reignat S, Brown D, Ogg GS, Jones L, Seneviratne SL, Williams R, et al. 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. 2004;78:5707–19.

    PubMed  CAS  Google Scholar 

  44. Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, King AS, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med. 2000;191:1269–80.

    PubMed  CAS  Google Scholar 

  45. Bertoletti A, Costanzo A, Chisari FV, Levrero M, Artini M, Sette A, Penna A, et al. 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. 1994;180:933–43.

    PubMed  CAS  Google Scholar 

  46. Rehermann B. Intrahepatic T, cells in hepatitis B: viral control versus liver cell injury. J Exp Med. 2000;191:1263–8.

    PubMed  CAS  Google Scholar 

  47. Han SH. Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis. 2004;8:403–18.

    PubMed  Google Scholar 

  48. Hosel M, Quasdorff M, Wiegmann K, Webb D, Zedler U, Broxtermann M, Tedjokusumo R, et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology. 2009;50:1773–82.

    PubMed  Google Scholar 

  49. Lucifora J, Durantel D, Testoni B, Hantz O, Levrero M, Zoulim F. Control of hepatitis B virus replication by innate response of HepaRG cells. Hepatology. 2010;51:63–72.

    PubMed  CAS  Google Scholar 

  50. Guy CS, Mulrooney-Cousins PM, Churchill ND, Michalak TI. Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. J Virol. 2008;82:8579–91.

    PubMed  CAS  Google Scholar 

  51. Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci U S A. 1990;87:6599–603.

    PubMed  CAS  Google Scholar 

  52. Chen MT, Billaud JN, Sallberg M, Guidotti LG, Chisari FV, Jones J, Hughes J, et al. 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. 2004;101:14913–8.

    PubMed  CAS  Google Scholar 

  53. Chen M, Sallberg M, Hughes J, Jones J, Guidotti LG, Chisari FV, Billaud JN, et al. Immune tolerance split between hepatitis B virus precore and core proteins. J Virol. 2005;79:3016–27.

    PubMed  CAS  Google Scholar 

  54. Locarnini S, Shaw T, Dean J, Colledge D, Thompson A, Li K, Lemon SM, et al. Cellular response to conditional expression of the hepatitis B virus precore and core proteins in cultured hepatoma (Huh-7) cells. J Clin Virol. 2005;32:113–21.

    PubMed  CAS  Google Scholar 

  55. Bertoletti A, Sette A, Chisari FV, Penna A, Levrero M, De Carli M, Fiaccadori F, et al. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994;369:407–10.

    PubMed  CAS  Google Scholar 

  56. Reignat S, Webster GJ, Brown D, Ogg GS, King A, Seneviratne SL, Dusheiko G, et al. Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. J Exp Med. 2002;195:1089–101.

    PubMed  CAS  Google Scholar 

  57. Yu S, Chen J, Wu M, Chen H, Kato N, Yuan Z. Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3. J Gen Virol. 2010;91:2080–90.

    PubMed  CAS  Google Scholar 

  58. Wang H, Ryu WS. Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS Pathog. 2010;6:e1000986.

    PubMed  Google Scholar 

  59. Wang X, Li Y, Mao A, Li C, Li Y, Tien P. Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-beta induction by disrupting the VISA-associated complex. Cell Mol Immunol. 2010;7:341–8.

    PubMed  CAS  Google Scholar 

  60. Hu Z, Zhang Z, Doo E, Coux O, Goldberg AL, Liang TJ. Hepatitis B virus X protein is both a substrate and a potential inhibitor of the proteasome complex. J Virol. 1999;73:7231–40.

    PubMed  CAS  Google Scholar 

  61. Wei C, Ni C, Song T, Liu Y, Yang X, Zheng Z, Jia Y, et al. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J Immunol. 2010;185:1158–68.

    PubMed  CAS  Google Scholar 

  62. Kumar M, Jung SY, Hodgson AJ, Madden CR, Qin J, Slagle BL. Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon. J Virol. 2011;85:987–95.

    PubMed  Google Scholar 

  63. Christen V, Duong F, Bernsmeier C, Sun D, Nassal M, Heim MH. Inhibition of alpha interferon signaling by hepatitis B virus. J Virol. 2007;81:159–65.

    PubMed  CAS  Google Scholar 

  64. Lutgehetmann M, Bornscheuer T, Volz T, Allweiss L, Bockmann JH, Pollok JM, Lohse AW, et al. Hepatitis B virus limits response of human hepatocytes to interferon-alpha in chimeric mice. Gastroenterology. 2011;140:2074–83, 2083e2071–2.

    Google Scholar 

  65. Carman WF, Boner W, Fattovich G, Colman K, Dornan ES, Thursz M, Hadziyannis S. Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission. J Infect Dis. 1997;175:1093–100.

    PubMed  CAS  Google Scholar 

  66. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxi A, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008;49:652–7.

    PubMed  Google Scholar 

  67. Candotti D, Grabarczyk P, Ghiazza P, Roig R, Casamitjana N, Iudicone P, Schmidt M, et al. Characterization of occult hepatitis B virus from blood donors carrying genotype A2 or genotype D strains. J Hepatol. 2008;49:537–47.

    PubMed  CAS  Google Scholar 

  68. Fan YF, Lu CC, Chen WC, Yao WJ, Wang HC, Chang TT, Lei HY, et al. Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection. Hepatology. 2001;33:277–86.

    PubMed  CAS  Google Scholar 

  69. Chaudhuri V, Tayal R, Nayak B, Acharya SK, Panda SK. Occult hepatitis B virus infection in chronic liver disease: full-length genome and analysis of mutant surface promoter. Gastroenterology. 2004;127:1356–71.

    PubMed  CAS  Google Scholar 

  70. Bes M, Vargas V, Piron M, Casamitjana N, Esteban JI, Vilanova N, Pinacho A, et al. T cell responses and viral variability in blood donation candidates with occult hepatitis B infection. J Hepatol. 2012;56:765–74.

    PubMed  CAS  Google Scholar 

  71. Hsu HY, Chang MH, Ni YH, Lin HH, Wang SM, Chen DS. Surface gene mutants of hepatitis B virus in infants who develop acute or chronic infections despite immunoprophylaxis. Hepatology. 1997;26:786–91.

    PubMed  CAS  Google Scholar 

  72. Carman WF, Trautwein C, van Deursen FJ, Colman K, Dornan E, McIntyre G, Waters J, et al. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology. 1996;24:489–93.

    PubMed  CAS  Google Scholar 

  73. Ghany MG, Ayola B, Villamil FG, Gish RG, Rojter S, Vierling JM, Lok AS. Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology. 1998;27:213–22.

    PubMed  CAS  Google Scholar 

  74. Heiberg IL, Winther TN, Paludan SR, Hogh B. Pattern recognition receptor responses in children with chronic hepatitis B virus infection. J Clin Virol. 2012;54:229–34.

    PubMed  Google Scholar 

  75. Kennedy PT, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, et al. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 2012;143:637–45.

    PubMed  CAS  Google Scholar 

  76. Rehermann B. Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses. Semin Liver Dis. 2007;27:152–60.

    PubMed  CAS  Google Scholar 

  77. Stross L, Gunther J, Gasteiger G, Asen T, Graf S, Aichler M, Esposito I, et al. Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice. Hepatology. 2012;56:873–83.

    PubMed  CAS  Google Scholar 

  78. Zhang M, Zhou J, Zhao T, Huang G, Tan Y, Tan S, Fu X, et al. Dissection of a circulating and intrahepatic CD4(+)Foxp3(+) T-cell subpopulation in chronic hepatitis B virus (HBV) infection: a highly informative strategy for distinguishing chronic HBV infection states. J Infect Dis. 2012;205:1111–20.

    PubMed  CAS  Google Scholar 

  79. Tang Y, Jiang L, Zheng Y, Ni B, Wu Y. Expression of CD39 on FoxP3+ T regulatory cells correlates with progression of HBV infection. BMC Immunol. 2012;13:17.

    PubMed  CAS  Google Scholar 

  80. Bonino F, Brunetto MR. Chronic hepatitis B e antigen (HBeAg) negative, anti-HBe positive hepatitis B: an overview. J Hepatol. 2003;39 Suppl 1:S160–3.

    PubMed  Google Scholar 

  81. Alexopoulou A, Baltayiannis G, Eroglu C, Nastos T, Dourakis SP, Archimandritis AJ, Karayiannis P. Core mutations in patients with acute episodes of chronic HBV infection are associated with the emergence of new immune recognition sites and the development of high IgM anti-HBc index values. J Med Virol. 2009;81:34–41.

    PubMed  Google Scholar 

  82. Ghosh S, Mondal RK, Banerjee P, Nandi M, Sarkar S, Das K, Santra A, et al. Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection. Clin Microbiol Infect. 2012;18:E412–8.

    PubMed  CAS  Google Scholar 

  83. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009–22.

    PubMed  CAS  Google Scholar 

  84. Aoki J, Kowazaki Y, Ohtsuki T, Okamoto R, Ohashi K, Hayashi S, Sakamaki H, et al. Kinetics of peripheral hepatitis B virus-specific CD8(+) T cells in patients with onset of viral reactivation. J Gastroenterol. 2013;48(6):728–37.

    PubMed  Google Scholar 

  85. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci U S A. 1986;83:1627–31.

    PubMed  CAS  Google Scholar 

  86. Roque-Afonso AM, Feray C, Samuel D, Simoneau D, Roche B, Emile JF, Gigou M, et al. Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver grafts from anti-HBc positive donors. Gut. 2002;50:95–9.

    Google Scholar 

  87. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911.

    PubMed  CAS  Google Scholar 

  88. Tsai SL, Chen PJ, Lai MY, Yang PM, Sung JL, Huang JH, Hwang LH, et al. 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. 1992;89:87–96.

    PubMed  CAS  Google Scholar 

  89. Yuen MF, Wong DK, Zheng BJ, Chan CC, Yuen JC, Wong BC, Lai CL. Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion. J Viral Hepat. 2007;14:269–75.

    PubMed  Google Scholar 

  90. Lau GK, Suri D, Liang R, Rigopoulou EI, Thomas MG, Mullerova I, Nanji A, et al. Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen. Gastroenterology. 2002;122:614–24.

    PubMed  CAS  Google Scholar 

  91. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123–9.

    PubMed  CAS  Google Scholar 

  92. Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol. 2006;101:297–303.

    PubMed  CAS  Google Scholar 

  93. Buster EH, Flink HJ, Cakaloglu Y, Simon K, Trojan J, Tabak F, So TM, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135:459–67.

    PubMed  CAS  Google Scholar 

  94. Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, Janssen HL. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137:2002–9.

    PubMed  CAS  Google Scholar 

  95. Hou J, Schilling R, Janssen HL, Hansen BE, Heijtink R, Sablon E, Williams R, et al. Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance. J Med Virol. 2007;79:1055–63.

    PubMed  CAS  Google Scholar 

  96. Naoumov NV, Thomas MG, Mason AL, Chokshi S, Bodicky CJ, Farzaneh F, Williams R, et al. Genomic variations in the hepatitis B core gene: a possible factor influencing response to interferon alfa treatment. Gastroenterology. 1995;108:505–14.

    PubMed  CAS  Google Scholar 

  97. Nair S, Perrillo RP. Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of pretreatment viremia? Hepatology. 2001;34:1021–6.

    PubMed  CAS  Google Scholar 

  98. Perrillo RP. Therapy of hepatitis B—viral suppression or eradication? Hepatology. 2006;43:S182–93.

    PubMed  CAS  Google Scholar 

  99. Fried MW, Piratvisuth T, Lau GK, Marcellin P, Chow WC, Cooksley G, Luo KX, et al. HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. Hepatology. 2008;47:428–34.

    PubMed  CAS  Google Scholar 

  100. Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, Germanidis G, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56:699–705.

    PubMed  CAS  Google Scholar 

  101. Zeuzem S, Gane E, Liaw YF, Lim SG, DiBisceglie A, Buti M, Chutaputti A, et al. Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B. J Hepatol. 2009;51:11–20.

    PubMed  CAS  Google Scholar 

  102. Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, Scognamiglio P, et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest. 1998;102:968–75.

    PubMed  CAS  Google Scholar 

  103. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, Cavalli A, et al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology. 2001;33:963–71.

    PubMed  CAS  Google Scholar 

  104. Mizukoshi E, Sidney J, Livingston B, Ghany M, Hoofnagle JH, Sette A, Rehermann B. Cellular immune responses to the hepatitis B virus polymerase. J Immunol. 2004;173:5863–71.

    PubMed  CAS  Google Scholar 

  105. Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano M, Schivazappa S, Alfieri A, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143:963–73e969.

    Google Scholar 

  106. Zhang NP, Reijnders JG, Perquin M, Hansen BE, Janssen HL. Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B. J Viral Hepat. 2011;18:e252–7.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stevan A. Gonzalez .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Gonzalez, S.A., Perrillo, R.P. (2014). Immunopathogenesis of Chronic Hepatitis B and the Clinical Events That Shape its Natural History. In: Gershwin, M., Vierling, J., Manns, M. (eds) Liver Immunology. Springer, Cham. https://doi.org/10.1007/978-3-319-02096-9_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-02096-9_14

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-02095-2

  • Online ISBN: 978-3-319-02096-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics