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Immunopathogenesis of Hepatitis B Virus (HBV) Infection

  • Fu-Sheng WangEmail author
  • Ji-Jing Shi
Chapter

Abstract

Though HBV itself is not cytopathic, the host immune responses associated with HBV infection determine the outcomes of HBV infection, either acute or chronic infection. Innate and adaptive arms of the immune system are usually involved in combating viral infection. During acute HBV infection, innate immunity is important for control of viral replication and dissemination at very early stage after HBV infection; subconsequently, adaptive immunity, especially vigorous, multi-specific and long-lasting HBV-specific T cellular immunity can further efficiently control viral infection. However, dysfunction is the hallmark of adaptive immunity during chronic infection, including faint humoral immunity and exhausted T cellular immunity. Host immune responses induced by HBV infection not only substantially drive disease progression, but also significantly influence efficacy of antiviral treatments in chronic HBV-infected individuals. Therefore, it is important to fully understand the course of immune pathogenesis and to find efficient immunotherapy plus nucleoside analogue(NUC) or IFN-α treatment to completely eliminate or functionally cure HBV infection. In this chapter, we summarizes the current progress in innate and adaptive immunities during acute or chronic HBV infection in humans.

Keywords

HBV Immunopathogenesis Infection Treatment 

References

  1. Asabe S, Wieland SF, Chattopadhyay PK, et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol. 2009;83(19):9652–62.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut. 2012;61(12):1754–64.PubMedCrossRefGoogle Scholar
  3. Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol. 2016;64(1 Suppl):S71–83.PubMedCrossRefGoogle Scholar
  4. Boettler T, Panther E, Bengsch B, et al. Expression of the interleukin-7 receptor alpha chain (CD127) on virus specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol. 2006;80(7):3532–40.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143(4):963–73.PubMedCrossRefGoogle Scholar
  6. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol. 2010;58(4):258–66.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Cooper A, Tal G, Lider O, et al. Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparin sulfate and involves TLR2. J Immunol. 2005;175(5):3165–76.PubMedCrossRefGoogle Scholar
  9. Cui X, Clark DN, Liu K, et al. Viral DNA-dependent induction of innate immune response to hepatitis B virus in immortalized mouse hepatocytes. J Virol. 2015;90(1):486–96.PubMedPubMedCentralCrossRefGoogle Scholar
  10. D’Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferon-alpha treatment in ‘immunotolerant’ children perinatally infected with hepatitis B: a pilot study. J Pediatr. 2006;148(2):228–33.PubMedCrossRefGoogle Scholar
  11. Dunn C, Peppa D, Khanna P, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology. 2009;137(4):1289–300.PubMedCrossRefGoogle Scholar
  12. Ferrari C. HBV and the immune response. Liver Int. 2015;35(Suppl 1):121–8.PubMedCrossRefGoogle Scholar
  13. Fisicaro P, Valdatta C, Boni C, et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut. 2009;58(7):974–82.PubMedCrossRefGoogle Scholar
  14. Fisicaro P, Valdatta C, Massari M, et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology. 2010;138(2):682–93.PubMedCrossRefGoogle Scholar
  15. Fisicaro P, Valdatta C, Massari M, et al. Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology. 2012;143(6):1576–85.PubMedCrossRefGoogle Scholar
  16. Franzese O, Kennedy PT, Gehring AJ, et al. Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J Virol. 2005;79(6):3322–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Iannacone M, Sitia G, Ruggeri ZM, et al. HBV pathogenesis in animal models: recent advances on the role of platelets. J Hepatol. 2007;46(4):719–26.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Kefalakes H, Budeus B, Walker A, et al. Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure. Hepatology. 2015;62(1):47–56.PubMedCrossRefGoogle Scholar
  19. Koh S, Bertoletti A. Circumventing failed antiviral immunity in chronic hepatitis B virus infection: triggering virus-specific or innate-like T cell response? Med Microbiol Immunol. 2015;204(1):87–94.PubMedCrossRefGoogle Scholar
  20. Kurktschiev PD, Raziorrouh B, Schraut W, et al. Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J Exp Med. 2014;211(10):2047–59.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Li Y, Ma S, Tang L, et al. Circulating chemokine (C-X-C Motif) receptor 5(+) CD4(+) T cells benefit hepatitis B e antigen seroconversion through IL-21 in patients with chronic hepatitis B virus infection. Hepatology. 2013;58(4):1277–86.PubMedCrossRefGoogle Scholar
  22. Liu Y, Li J, Chen J, et al. Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways. J Virol. 2015;89(4):2287–300.PubMedCrossRefGoogle Scholar
  23. Liu Y, Cheng LS, Wu SD, et al. IL-10-producing regulatory B-cells suppressed effector T-cells but enhanced regulatory T-cells in chronic HBV infection. Clin Sci (Lond). 2016;130(11):907–19.CrossRefGoogle Scholar
  24. Lopes AR, Kellam P, Das A, et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J Clin Invest. 2008;118(5):1835–45.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Loqqi E, Bihl FK, Cursaro C, et al. Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels. PLoS One. 2013;8(6):e65327.CrossRefGoogle Scholar
  26. Lunemann S, Malone DF, Hengst J, et al. Compromised function of natural killer cells in acute and chronic viral hepatitis. J Infect Dis. 2014;209(9):1362–73.PubMedCrossRefGoogle Scholar
  27. Ma Z, Zhang E, Yang D, et al. Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses. Cell Mol Immunol. 2015;12(3):273–82.PubMedCrossRefGoogle Scholar
  28. Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment of HBV infection. J Hepatol. 2016;64(1 Suppl):S60–70.PubMedCrossRefGoogle Scholar
  29. Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol. 2013;4:57.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Martinet J, Dufeu-Duchesne T, Bruder Costa J, et al. Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection. Gastroenterology. 2012;143(6):1586–96.PubMedCrossRefGoogle Scholar
  31. Nebbia G, Peppa D, Schurich A, et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS One. 2012;7(10):e47648.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Ni Y, Lempp FA, Mehrle S, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014;146(4):1070–83.PubMedCrossRefGoogle Scholar
  33. Pallett LJ, Gill US, Quaglia A, et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med. 2015;21(6):591–600.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Peppa D, Micco L, Javaid A, et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog. 2010;6(12):e1001227.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Peppa D, Gill US, Reynolds G, et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell mediated deletion. J Exp Med. 2013;210(1):99–114.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Raziorrouh B, Heeg M, Kurktschiev P, et al. Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules. PLoS One. 2014;9(8):e105703.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Rehermann B, Fowler P, Sidney J, 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(3):1047–58.PubMedCrossRefGoogle Scholar
  38. Schurich A, Pallett LJ, Lubowiecki M, et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog. 2013;9(3):e1003208.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16(8):509–23.PubMedCrossRefGoogle Scholar
  40. Stoop JN, Claassen MA, Woltman AM, et al. Intrahepatic regulatory T cells are phenotypically distinct from their peripheral counterparts in chronic HBV patients. Clin Immunol. 2008;129(3):419–27.PubMedCrossRefGoogle Scholar
  41. Sun C, Fu B, Gao Y, et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog. 2012;8(3):e1002594.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Wang FS, Zhang Z. Host immunity influences disease progression and antiviral efficacy in humans infected with hepatitis B virus. Expert Rev Gastroenterol Hepatol. 2009;3(5):499–512.PubMedCrossRefGoogle Scholar
  43. Wei C, Ni C, Song T, et al. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J Immunol. 2010;185(2):1158–68.PubMedCrossRefGoogle Scholar
  44. Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27(4):670–84.PubMedCrossRefGoogle Scholar
  45. Wu SF, Wang WJ, Gao YQ. Natural killer cells in hepatitis B virus infection. Braz J Infect Dis. 2015;19(4):417–25.PubMedCrossRefGoogle Scholar
  46. Xu X, Shang Q, Chen X, et al. Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients. Cell Mol Immunol. 2015;12(3):309–16.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Ye B, Liu X, Li X, et al. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis. 2015;6:e1694.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Zhang Z, Zhang JY, Wang LF, et al. Immunopathogenesis and prognostic immune markers of chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2012;27(2):223–30.PubMedCrossRefGoogle Scholar
  49. Zhao J, Li Y, Jin L, et al. Natural killer cells are characterized by the concomitantly increased interferon-gamma and cytotoxicity in acute resolved hepatitis B patients. PLoS One. 2012;7(11):e49135.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Treatment and Research Center for Infectious Diseases, Beijing 302 HospitalBeijingChina

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