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Immunopathogenesis of hepatitis B persistent infection: implications for immunotherapeutic strategies

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Abstract

It has been shown that cellular immunity, especially by cytotoxic T lymphocytes (CTLs), NK cells and NK-T cells, plays a central role in the control of virus infection. In addition, CD4+ T cells facilitate both CTL and B-cell responses. Hyporesponsiveness of HBV-specific T cells in peripheral blood has been shown in patients with chronic HBV infection. Interferon and nucleos(t)ide analogs, such as lamivudine, adefovir, entecavir and tenofovir, are the currently available treatments. Unfortunately, the efficacy of nucleos(t)ide analogs is limited by viral reactivation by the emergence of escaped mutants in cases of prolonged treatment. Therefore, immunotherapy is one of the significant options to eradicate or control HBV replication without drugs. The aim of immunotherapies is to decrease the levels of viral replication and to eradicate infected hepatocytes. For this reason, new strategies for immunotherapies by vaccination target not only the induction or stimulation of CD4+ and CD8+ T cell responses, but also the induction of proinflammatory cytokines capable of controlling viral replication. We will review the immunopathogenesis of persistent HBV infection, especially focusing on the mechanisms of immune suppression. Then we will review the immunotherapy for HBV persistent infection.

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References

  1. Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature. 1985;317:489–95.

    Article  CAS  PubMed  Google Scholar 

  2. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. 2003;362:2089–94.

    Article  CAS  PubMed  Google Scholar 

  3. Kagi D, Ledermann B, Burki K, Zinkernagel RM, Hengartner H. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annu Rev Immunol. 1996;14:207–32.

    Article  CAS  PubMed  Google Scholar 

  4. Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med. 2000;192:921–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lohr HF, Krug S, Herr W, Weyer S, Schlaak J, Wolfel T, et al. Quantitative and functional analysis of core-specific T-helper cell and CTL activities in acute and chronic hepatitis B. Liver. 1998;18:405–13.

    Article  CAS  PubMed  Google Scholar 

  6. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol. 1995;13:29–60.

    Article  CAS  PubMed  Google Scholar 

  7. Reignat S, Webster GJ, Brown D, Ogg GS, King A, Seneviratne SL, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77:4911–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27:670–84.

    Article  CAS  PubMed  Google Scholar 

  10. Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis. 2007;7:804–13.

    Article  CAS  PubMed  Google Scholar 

  11. Peng G, Li S, Wu W, Sun Z, Chen Y, Chen Z. Circulating CD4+CD25+ regulatory T cells correlate with chronic hepatitis B infection. Immunology. 2008;123:57–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barboza L, Salmen S, Goncalves L, Colmenares M, Peterson D, Montes H, et al. Antigen-induced regulatory T cells in HBV chronically infected patients. Virology. 2007;368:41–9.

    Article  CAS  PubMed  Google Scholar 

  13. Stoop JN, van der Molen RG, Kuipers EJ, Kusters JG, Janssen HL. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology. 2007;361:141–8.

    Article  CAS  PubMed  Google Scholar 

  14. Kondo Y, Kobayashi K, Ueno Y, Shiina M, Niitsuma H, Kanno N, et al. Mechanism of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B. World J Gastroenterol. 2006;12:4310–7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 2006;177:739–47.

    Article  CAS  PubMed  Google Scholar 

  16. Das A, Hoare M, Davies N, Lopes AR, Dunn C, Kennedy PT, et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med. 2008;205:2111–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mohanty SR, Kupfer SS, Khiani V. Treatment of chronic hepatitis B. Nat Clin Pract Gastroenterol Hepatol. 2006;3:446–58.

    Article  CAS  PubMed  Google Scholar 

  18. Langley DR, Walsh AW, Baldick CJ, Eggers BJ, Rose RE, Levine SM, et al. Inhibition of hepatitis B virus polymerase by entecavir. J Virol. 2007;81:3992–4001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zoulim F. Entecavir: a new treatment option for chronic hepatitis B. J Clin Virol. 2006;36:8–12.

    Article  CAS  PubMed  Google Scholar 

  20. Tong MJ, Tu SS. Treatment of patients with chronic hepatitis B with adefovir dipivoxil. Semin Liver Dis. 2004;24(Suppl 1):37–44.

    Article  CAS  PubMed  Google Scholar 

  21. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology. 1998;27:1670–7.

    Article  CAS  PubMed  Google Scholar 

  22. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005;434:772–7.

    Article  CAS  PubMed  Google Scholar 

  23. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–7.

    Article  CAS  PubMed  Google Scholar 

  24. Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005;436:709–13.

    Article  CAS  PubMed  Google Scholar 

  25. Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature. 2000;405:537–43.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Fisicaro P, Valdatta C, Boni C, Massari M, Mori C, Zerbini A, et al. Early kinetics of innate and adaptive immune responses during Hepatitis B virus infection. Gut. 2009 (in press).

  28. Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med. 2007;204:667–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vilarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA. 2007;104:18187–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis. 1995;20:992–1000.

    Article  CAS  PubMed  Google Scholar 

  31. Wu J, Meng Z, Jiang M, Pei R, Trippler M, Broering R, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology. 2008 (in press).

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Tsui LV, Guidotti LG, Ishikawa T, Chisari FV. Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. Proc Natl Acad Sci USA. 1995;92:12398–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bertoletti A, Ferrari C, Fiaccadori F, Penna A, Margolskee R, Schlicht HJ, et al. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci USA. 1991;88:10445–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ferrari C, Penna A, Bertoletti A, Valli A, Antoni AD, Giuberti T, 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.

    CAS  PubMed  Google Scholar 

  36. Kondo Y, Kobayashi K, Asabe S, Shiina M, Niitsuma H, Ueno Y, et al. Vigorous response of cytotoxic T lymphocytes associated with systemic activation of CD8 T lymphocytes in fulminant hepatitis B. Liver Int. 2004;24:561–7.

    Article  CAS  PubMed  Google Scholar 

  37. Battegay M, Moskophidis D, Waldner H, Brundler MA, Fung-Leung WP, Mak TW, et al. Impairment and delay of neutralizing antiviral antibody responses by virus-specific cytotoxic T cells. J Immunol. 1993;151:5408–15.

    CAS  PubMed  Google Scholar 

  38. Kakimi K, Isogawa M, Chung J, Sette A, Chisari FV. Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: implications for immunotherapy of persistent viral infections. J Virol. 2002;76:8609–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rehermann B, Fowler P, Sidney J, Person J, Redeker A, Brown M, 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.

    Article  CAS  PubMed  Google Scholar 

  41. Nayersina R, Fowler P, Guilhot S, Missale G, Cerny A, Schlicht HJ, 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.

    CAS  PubMed  Google Scholar 

  42. Sidney J, Asabe S, Peters B, Purton KA, Chung J, Pencille TJ, et al. Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules. Immunogenetics. 2006;58:559–70.

    Article  CAS  PubMed  Google Scholar 

  43. Sobao Y, Tomiyama H, Sugi K, Tokunaga M, Ueno T, Saito S, et al. The role of hepatitis B virus-specific memory CD8 T cells in the control of viral replication. J Hepatol. 2002;36:105–15.

    Article  PubMed  Google Scholar 

  44. Sobao Y, Sugi K, Tomiyama H, Saito S, Fujiyama S, Morimoto M, et al. 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. 2001;34:922–9.

    Article  CAS  PubMed  Google Scholar 

  45. Blackburn SD, Wherry EJ. IL-10, T cell exhaustion and viral persistence. Trends Microbiol. 2007;15:143–6.

    Article  CAS  PubMed  Google Scholar 

  46. Khakoo SI, Ling R, Scott I, Dodi AI, Harrison TJ, Dusheiko GM, et al. Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals. Gut. 2000;47:137–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cerny A, Chisari FV. Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology. 1999;30:595–601.

    Article  CAS  PubMed  Google Scholar 

  48. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, et al. T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J. 2006;25:2623–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Keir ME, Latchman YE, Freeman GJ, Sharpe AH. Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol. 2005;175:7372–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Riley JL, June CH. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood. 2005;105:13–21.

    Article  CAS  PubMed  Google Scholar 

  52. Peng G, Li S, Wu W, Tan X, Chen Y, Chen Z. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol. 2008;45:963–70.

    Article  CAS  PubMed  Google Scholar 

  53. Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. J Immunol. 2007;178:2714–20.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang Z, Zhang JY, Wherry EJ, Jin B, Xu B, Zou ZS, et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology. 2008;134:1938–49, 1949 e1–3.

    Article  PubMed  Google Scholar 

  55. Kelsall BL, Stuber E, Neurath M, Strober W. Interleukin-12 production by dendritic cells. The role of CD40–CD40L interactions in Th1 T-cell responses. Ann N Y Acad Sci. 1996;795:116–26.

    Article  CAS  PubMed  Google Scholar 

  56. Battegay M, Moskophidis D, Rahemtulla A, Hengartner H, Mak TW, Zinkernagel RM. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J Virol. 1994;68:4700–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hunziker L, Klenerman P, Zinkernagel RM, Ehl S. Exhaustion of cytotoxic T cells during adoptive immunotherapy of virus carrier mice can be prevented by B cells or CD4+ T cells. Eur J Immunol. 2002;32:374–82.

    Article  CAS  PubMed  Google Scholar 

  58. Habicht A, Kewalaramani R, Vu MD, Demirci G, Blazar BR, Sayegh MH, et al. Striking dichotomy of PD-L1 and PD-L2 pathways in regulating alloreactive CD4(+) and CD8(+) T cells in vivo. Am J Transplant. 2007;7:2683–92.

    Article  CAS  PubMed  Google Scholar 

  59. Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S, Berical A, et al. High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J Virol. 2008;82:3154–60.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Haydon GH, Mutimer DJ. Hepatitis B and C virus infections in the immune compromised. Curr Opin Infect Dis. 2003;16:473–9.

    Article  CAS  PubMed  Google Scholar 

  62. Haverkamp M, Smit M, Weersink A, Boucher CA, Hoepelman AI. The effect of lamivudine on the replication of hepatitis B virus in HIV-infected patients depends on the host immune status (CD4 cell count). AIDS. 2003;17:1572–4.

    Article  PubMed  Google Scholar 

  63. Suri-Payer E, Amar AZ, Thornton AM, Shevach EM. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol. 1998;160:1212–8.

    CAS  PubMed  Google Scholar 

  64. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.

    Article  CAS  PubMed  Google Scholar 

  66. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT. CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med. 2003;198:889–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172:834–42.

    Article  CAS  PubMed  Google Scholar 

  68. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural and induced CD4+CD25+ cells educate CD4+CD25− cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol. 2004;172:5213–21.

    Article  CAS  PubMed  Google Scholar 

  69. Tavakoli S, Schwerin W, Rohwer A, Hoffmann S, Weyer S, Weth R, et al. Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection. J Gen Virol. 2004;85:2829–36.

    Article  CAS  PubMed  Google Scholar 

  70. van der Molen RG, Sprengers D, Binda RS, de Jong EC, Niesters HG, Kusters JG, et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology. 2004;40:738–46.

    Article  PubMed  Google Scholar 

  71. Op den Brouw ML, Binda RS, van Roosmalen MH, Protzer U, Janssen HL, van der Molen RG, et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology. 2009;126:280–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Beckebaum S, Cicinnati VR, Zhang X, Ferencik S, Frilling A, Grosse-Wilde H, et al. Hepatitis B virus-induced defect of monocyte-derived dendritic cells leads to impaired T helper type 1 response in vitro: mechanisms for viral immune escape. Immunology. 2003;109:487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hu GF, Wu XB, Yu SY, Kang Y, Hou YD. Functional change of human peripheral blood monocyte-derived dendritic cells after recombinant adeno-associated virus type 2-mediated HBsAg gene infection. Di Yi Jun Yi Da Xue Xue Bao. 2003;23:696–8. 701.

    CAS  PubMed  Google Scholar 

  74. Arima S, Akbar SM, Michitaka K, Horiike N, Nuriya H, Kohara M, et al. Impaired function of antigen-presenting dendritic cells in patients with chronic hepatitis B: localization of HBV DNA and HBV RNA in blood DC by in situ hybridization. Int J Mol Med. 2003;11:169–74.

    CAS  PubMed  Google Scholar 

  75. Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. J Immunol. 2002;169:5188–95.

    Article  PubMed  Google Scholar 

  76. Bertolino P, Bowen DG, McCaughan GW, Fazekas de St Groth B. Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol. 2001;166:5430–8.

    Article  CAS  PubMed  Google Scholar 

  77. Guan R. Interferon monotherapy in chronic hepatitis B. J Gastroenterol Hepatol. 2000;15(Suppl):E34–40.

    Article  CAS  PubMed  Google Scholar 

  78. Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003;125:292–7.

    Article  PubMed  Google Scholar 

  79. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119:172–80.

    Article  CAS  PubMed  Google Scholar 

  80. Akbar SM, Horiike N, Onji M. Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection. World J Gastroenterol. 2006;12:2876–83.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Pol S, Michel ML. Therapeutic vaccination in chronic hepatitis B virus carriers. Expert Rev Vaccines. 2006;5:707–16.

    Article  CAS  PubMed  Google Scholar 

  82. Michel ML, Mancini-Bourgine M. Therapeutic vaccination against chronic hepatitis B virus infection. J Clin Virol. 2005;34(Suppl 1):S108–14.

    Article  CAS  PubMed  Google Scholar 

  83. Yu AS, Cheung RC, Keeffe EB. Hepatitis B vaccines. Clin Liver Dis. 2004;8:283–300.

    Article  PubMed  Google Scholar 

  84. Michel ML, Pol S, Brechot C, Tiollais P. Immunotherapy of chronic hepatitis B by anti HBV vaccine: from present to future. Vaccine. 2001;19:2395–9.

    Article  CAS  PubMed  Google Scholar 

  85. Safadi R, Israeli E, Papo O, Shibolet O, Melhem A, Bloch A, et al. Treatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins. Am J Gastroenterol. 2003;98:2505–15.

    Article  CAS  PubMed  Google Scholar 

  86. Wen YM, Wu XH, Hu DC, Zhang QP, Guo SQ. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet. 1995;345:1575–6.

    Article  CAS  PubMed  Google Scholar 

  87. Dahmen A, Herzog-Hauff S, Bocher WO, Galle PR, Lohr HF. Clinical and immunological efficacy of intradermal vaccine plus lamivudine with or without interleukin-2 in patients with chronic hepatitis B. J Med Virol. 2002;66:452–60.

    Article  CAS  PubMed  Google Scholar 

  88. Horiike N, Fazle Akbar SM, Michitaka K, Joukou K, Yamamoto K, Kojima N, et al. In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol. 2005;32:156–61.

    Article  CAS  PubMed  Google Scholar 

  89. Akbar F, Yoshida O, Abe M, Hiasa Y, Onji M. Engineering immune therapy against hepatitis B virus. Hepatol Res. 2007;37(Suppl 3):S351–6.

    Article  CAS  PubMed  Google Scholar 

  90. Roy MJ, Wu MS, Barr LJ, Fuller JT, Tussey LG, Speller S, et al. Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine. Vaccine. 2000;19:764–78.

    Article  CAS  PubMed  Google Scholar 

  91. Rottinghaus ST, Poland GA, Jacobson RM, Barr LJ, Roy MJ. Hepatitis B DNA vaccine induces protective antibody responses in human non-responders to conventional vaccination. Vaccine. 2003;21:4604–8.

    Article  CAS  PubMed  Google Scholar 

  92. Mancini-Bourgine M, Fontaine H, Scott-Algara D, Pol S, Brechot C, Michel ML. Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology. 2004;40:874–82.

    Article  CAS  PubMed  Google Scholar 

  93. Mancini-Bourgine M, Fontaine H, Brechot C, Pol S, Michel ML. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine. 2006;24:4482–9.

    Article  CAS  PubMed  Google Scholar 

  94. Yang SH, Lee CG, Park SH, Im SJ, Kim YM, Son JM, et al. Correlation of antiviral T-cell responses with suppression of viral rebound in chronic hepatitis B carriers: a proof-of-concept study. Gene Ther. 2006;13:1110–7.

    Article  CAS  PubMed  Google Scholar 

  95. Vitiello A, Ishioka G, Grey HM, Rose R, Farness P, LaFond R, et al. Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection I. Induction of a primary cytotoxic T lymphocyte response in humans. J Clin Invest. 1995;95:341–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Inchauspe G, Michel ML. Vaccines and immunotherapies against hepatitis B and hepatitis C viruses. J Viral Hepat. 2007;14(Suppl 1):97–103.

    Article  PubMed  Google Scholar 

  97. Weeratna RD, Makinen SR, McCluskie MJ, Davis HL. TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848). Vaccine. 2005;23:5263–70.

    Article  CAS  PubMed  Google Scholar 

  98. Horsmans Y, Berg T, Desager JP, Mueller T, Schott E, Fletcher SP, et al. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology. 2005;42:724–31.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported in part from Health and Labour Sciences Research Grants for the Research on Measures for Intractable Diseases (from the Ministry of Health, Labour and Welfare of Japan).

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Kondo, Y., Ueno, Y. & Shimosegawa, T. Immunopathogenesis of hepatitis B persistent infection: implications for immunotherapeutic strategies. Clin J Gastroenterol 2, 71–79 (2009). https://doi.org/10.1007/s12328-009-0074-z

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