Immunological cure of HBV infection

  • Julia Lang
  • Christoph Neumann-Haefelin
  • Robert Thimme
Review Article


Chronic hepatitis B virus (HBV) infection is a major global health burden and cure is rarely achieved by current antiviral therapies. Therefore, there is an urgent need for new therapeutic options. Immune modulation with the goal to restore dysfunctional HBV-specific immunity is an interesting target for new therapeutic strategies. Based on the current evidence on immunology in resolving and persistent HBV infection, we will review the growing field of immunotherapeutic approaches for treatment of chronic HBV infection. We will also discuss the challenge of a heterogeneous patient population and personalized treatment as a possible key factor of success.

Graphical abstract


Adaptive immunity CD4+ T-lymphocytes CD8+ T-lymphocytes Hepatitis B Immunotherapy 


Compliance with ethical standards

Compliance with ethical requirements

This article does not contain any studies with human or animal subjects.

Conflict of interest

Julia Lang, Christoph Neumann-Haefelin and Robert Thimme declare that they have no competing interests.


  1. 1.
    Agarwal K, Ahn SH, Elkhashab M, Lau AH, Gaggar A, Bulusu A, et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. J Viral Hepat 2018;25:1331–1340PubMedCrossRefGoogle Scholar
  2. 2.
    Alberti A, Diana S, Sculard GH, Eddleston AL, Williams R. Detection of a new antibody system reacting with Dane particles in hepatitis B virus infection. Br Med J 1978;2:1056–1058PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH, et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 2009;83:9652–9662PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Balkow S, Kersten A, Tran TTT, Stehle T, Grosse P, Museteanu C, et al. Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. J Virol 2001;75:8781–6791PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol 2014;61:1212–1219.PubMedCrossRefGoogle Scholar
  6. 6.
    Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016;64:S71–S83PubMedCrossRefGoogle Scholar
  7. 7.
    Bertoletti A, Tan AT, Koh S. T-cell therapy for chronic viral hepatitis. Cytotherapy 2017;19:1317–1324PubMedCrossRefGoogle Scholar
  8. 8.
    Meyer Zum Büschenfelde KH, Löhr HF. Regulation of the neutralizing anti-hepatitis B surface (HBs) antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV) infection. Clin Exp Immunol 1996;105:52–58PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, 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;80:3532–3540PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007;81:4215–4225PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Boni C, Laccabue D, Lampertico P, Giuberti T, Viganò M, Schivazappa S, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012;143:963.e9–973.e9CrossRefGoogle Scholar
  12. 12.
    Boni C, Vecchi A, Rossi M, Laccabue D, Giuberti T, Alfieri A, et al. TLR7 agonist increases responses of hepatitis B virus-specific T cells and natural killer cells in patients with chronic hepatitis B treated with nucleos(t)ide analogues. Gastroenterology 2018;154:1764.e7–1777.e7CrossRefGoogle Scholar
  13. 13.
    Cheng X, Xia Y, Serti E, Block PD, Chung M, Chayama K, et al. Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages. Hepatol Baltim Md 2017;66:1779–1793.CrossRefGoogle Scholar
  14. 14.
    Chu C-M, Liaw Y-F. Hepatitis B surface antigen seroclearance during chronic HBV infection. Antivir Ther 2010;15:133–143PubMedCrossRefGoogle Scholar
  15. 15.
    Cornberg M, Höner Zu Siederdissen C. HBsAg seroclearance with NUCs: rare but important. Gut 2014;63:1208–1209.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Das A, Ellis G, Pallant C, Lopes AR, Khanna P, Peppa D, et al. IL-10–producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol 2012;189:3925–3935PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Dembek C, Protzer U, Roggendorf M. Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination. Curr Opin Virol 2018;30:58–67PubMedCrossRefGoogle Scholar
  18. 18.
    Desmond CP, Gaudieri S, James IR, Pfafferott K, Chopra A, Lau GK, et al. Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV) infection, and adaptation is greatest in HBV e antigen-negative disease. J Virol 2012;86:1181–1192.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Diepolder HM, Jung MC, Keller E, Schraut W, Gerlach JT, Grüner N, et al. A vigorous virus-specific CD4+ T cell response may contribute to the association of HLA-DR13 with viral clearance in hepatitis B. Clin Exp Immunol 1998;113:244–251PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Dunn C, Peppa D, Khanna P, Nebbia G, Jones M, Brendish N, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 2009;137:1289–1300PubMedCrossRefGoogle Scholar
  21. 21.
    El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492–2502PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    European Association for the Study of the Liver. Electronic address:, and European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370–98CrossRefGoogle Scholar
  23. 23.
    Evens AM, Jovanovic BD, Su Y-C, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol 2011;22:1170–1180PubMedCrossRefGoogle Scholar
  24. 24.
    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;58:974–982PubMedCrossRefGoogle Scholar
  25. 25.
    Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 2010;138(2):682–693.e4PubMedCrossRefGoogle Scholar
  26. 26.
    Fisicaro P, Barili V, Montanini B, Acerbi G, Ferracin M, Guerrieri F, et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med 2017;23:327–336PubMedCrossRefGoogle Scholar
  27. 27.
    Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006;1:23–61PubMedCrossRefGoogle Scholar
  28. 28.
    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;284:825–829PubMedCrossRefGoogle Scholar
  29. 29.
    Hadziyannis SJ. Natural history of chronic hepatitis B in Euro-Mediterranean and African countries. J Hepatol 2011;55:183–191PubMedCrossRefGoogle Scholar
  30. 30.
    Hoh A, Heeg M, Ni Y, Schuch A, Binder B, Hennecke N, et al. Hepatitis B virus-infected HepG2hNTCP cells serve as a novel immunological tool to analyze the antiviral efficacy of CD8+ T cells in vitro. J Virol 2015;89:7433–7438PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Hösel M, Quasdorff M, Wiegmann K, Webb D, Zedler U, Broxtermann M, et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatol Baltim Md 2009;50:1773–1782CrossRefGoogle Scholar
  32. 32.
    Iannacone M, Sitia G, Ruggeri ZM, Guidotti LG. HBV pathogenesis in animal models: recent advances on the role of platelets. J Hepatol 2007;46:719–726PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016;537:417–421PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kah J, Koh S, Volz T, Ceccarello E, Allweiss L, Lütgehetmann M, et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J Clin Investig 2017;127:3177–3188PubMedCrossRefGoogle Scholar
  35. 35.
    Kefalakes H, Budeus B, Walker A, Jochum C, Hilgard G, Heinold A, et al. Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure. Hepatol Baltim Md 2015;62:47–56CrossRefGoogle Scholar
  36. 36.
    Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, et al. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology 2012;143:637–645PubMedCrossRefGoogle Scholar
  37. 37.
    Koh S, Kah J, Tham CYL, Yang N, Ceccarello E, Chia A, et al. Nonlytic lymphocytes engineered to express virus-specific T-cell receptors limit HBV infection by activating APOBEC3. Gastroenterology 2018;155:180–193.e6PubMedCrossRefGoogle Scholar
  38. 38.
    Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013;144(1508–1517):1517.e1–1517.e10Google Scholar
  39. 39.
    Lee YB, Lee J-H, Kim YJ, Yoon J-H, Lee H-S. The effect of therapeutic vaccination for the treatment of chronic hepatitis B virus infection. J Med Virol 2015;87:575–582PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Li L, Barry V, Daffis S, Niu C, Huntzicker E, French DM, et al. Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells. J Hepatol 2018;68:912–921PubMedCrossRefGoogle Scholar
  41. 41.
    Lim K-H, Park E-S, Kim DH, Cho KC, Kim KP, Park YK, et al. Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5’-UTR of TRIM22. Gut 2018;67:166–178PubMedCrossRefGoogle Scholar
  42. 42.
    Liu J, Zhang E, Ma Z, Wu W, Kosinska A, Zhang X, et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog 2014;10:e1003856PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Liu Y, Cheng L-S, Wu S, Wang S-Q, Li L, She W-M, et al. IL-10-producing regulatory B-cells suppressed effector T-cells but enhanced regulatory T-cells in chronic HBV infection. Clin Sci Lond Engl 2016;1979(130):907–919CrossRefGoogle Scholar
  44. 44.
    Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. J Hepatol 2017;67:847–861PubMedCrossRefGoogle Scholar
  45. 45.
    Madaliński K, Bragiel I. HBsAg immune complexes in the course of infection with hepatitis B virus. Clin Exp Immunol 1979;36:371–378PubMedPubMedCentralGoogle Scholar
  46. 46.
    Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment of HBV infection. J Hepatol 2016;64:S60–S70PubMedCrossRefGoogle Scholar
  47. 47.
    Maini MK, Pallett LJ. Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand. Lancet Gastroenterol Hepatol 2018;3:192–202PubMedCrossRefGoogle Scholar
  48. 48.
    Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 1999;117:1386–1396PubMedCrossRefGoogle Scholar
  49. 49.
    Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381:468–475PubMedCrossRefGoogle Scholar
  50. 50.
    Menne S, Tumas DB, Liu KH, Thampi L, AlDeghaither D, Baldwin BH, et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol 2015;62:1237–1245PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Mohamadkhani A, Naderi E, Sotoudeh M, Katoonizadeh A, Montazeri G, Poustchi H. Clinical feature of intrahepatic B-lymphocytes in chronic hepatitis B. Int J Inflamm 2014;2014:896864CrossRefGoogle Scholar
  52. 52.
    Mutz P, Metz P, Lempp FA, Bender S, Qu B, Schöneweis K, et al. HBV bypasses the innate immune response and does not protect HCV from antiviral activity of interferon. Gastroenterology 2018;154:1791.e22–1804.e22CrossRefGoogle Scholar
  53. 53.
    Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 2015;64:1972–1984PubMedCrossRefGoogle Scholar
  54. 54.
    Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009;137(1151–1160):1160.e1–1160.e7Google Scholar
  55. 55.
    Oliviero B, Cerino A, Varchetta S, Paudice E, Pai S, Ludovisi S, et al. Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections. J Hepatol 2011;55:53–60PubMedCrossRefGoogle Scholar
  56. 56.
    Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 2012;338:1220–1225PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016;354:1160–1165PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Paul S, Dickstein A, Saxena A, Terrin N, Viveiros K, Balk EM, et al. Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: a meta-analysis. Hepatol Baltim Md 2017;66:379–388CrossRefGoogle Scholar
  59. 59.
    Ravi S, Spencer K, Ruisi M, Ibrahim N, Luke JJ, Thompson JA, et al. Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series. J Immunother Cancer 2014;2:33PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Raziorrouh B, Schraut W, Gerlach T, Nowack D, Grüner NH, Ulsenheimer A, et al. The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function. Hepatol Baltim Md 2010;52:1934–1947CrossRefGoogle Scholar
  61. 61.
    Raziorrouh B, Heeg M, Kurktschiev P, Schraut W, Zachoval R, Wendtner C, 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:e105703PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    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 Investig 1995;96:1527–1534PubMedCrossRefGoogle Scholar
  63. 63.
    Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5(3):215–229PubMedCrossRefGoogle Scholar
  64. 64.
    Rivino L, Bert NL, Gill US, Kunasegaran K, Cheng Y, Tan DZM, et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Investig 2018;128:668–681PubMedCrossRefGoogle Scholar
  65. 65.
    Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, Chen DS, Chen HL, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1–98PubMedCrossRefGoogle Scholar
  66. 66.
    Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 2015;42:123–132PubMedCrossRefGoogle Scholar
  67. 67.
    Schurich A, Khanna P, Lopes AR, Han KJ, Peppa D, Micco L, et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection. Hepatol Baltim Md 2011;53:1494–1503CrossRefGoogle Scholar
  68. 68.
    Schurich A, Pallett LJ, Jajbhay D, Wijngaarden J, Otano I, Gill US, et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep 2016;16:1243–1252PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet Lond Engl 2015;386:1546–1555CrossRefGoogle Scholar
  70. 70.
    Seto W-K, Chan TSY, Hwang Y-Y, Wong DK-H, Fung J, Liu KS-H, et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J Clin Oncol 2014;32:3736–3743PubMedCrossRefGoogle Scholar
  71. 71.
    Seto W-K, Cheung K-S, Wong DK-H, Huang F-Y, Fung J, Liu KS-H, Let al. Hepatitis B surface antigen seroclearance during nucleoside analogue therapy: surface antigen kinetics, outcomes, and durability. J Gastroenterol 2016;51:487–495PubMedCrossRefGoogle Scholar
  72. 72.
    Shin E-C, Sung PS, Park S-H. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol 2016;16:509–523PubMedCrossRefGoogle Scholar
  73. 73.
    Singh AK, Rooge SB, Varshney A, Vasudevan M, Bhardwaj A, Venugopal SK, et al. Global microRNA expression profiling in the liver biopsies of hepatitis B virus-infected patients suggests specific microRNA signatures for viral persistence and hepatocellular injury. Hepatol Baltim Md 2018;67:1695–709CrossRefGoogle Scholar
  74. 74.
    Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B? J Hepatol 2013;58:205–209PubMedCrossRefGoogle Scholar
  75. 75.
    Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003;77:68–76PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Thomsen MK, Nandakumar R, Stadler D, Malo A, Valls RM, Wang F, et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatol Baltim Md 2016;64:746–759CrossRefGoogle Scholar
  77. 77.
    van den Ende C, Marano C, van Ahee A, Bunge EM, De Moerlooze L. The immunogenicity of GSK’s recombinant hepatitis B vaccine in children: a systematic review of 30 years of experience. Expert Rev Vaccines 2017;16:789–809PubMedCrossRefGoogle Scholar
  78. 78.
    Vanwolleghem T, Hou J, van Oord G, Andeweg AC, Osterhaus ADME, Pas SD, et al. Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells. Hepatol Baltim Md 2015;62:87–100CrossRefGoogle Scholar
  79. 79.
    Verrier ER, Yim S-A, Heydmann L, El Saghire H, Bach C, Turon-Lagot V, et al. Hepatitis B virus evasion from cyclic guanosine monophosphate-adenosine monophosphate synthase sensing in human hepatocytes. Md: Hepatol Baltim; 2018CrossRefGoogle Scholar
  80. 80.
    Wang R, Xie R, Song Z. Circulating regulatory Tfh cells are enriched in patients with chronic hepatitis B infection and induce the differentiation of regulatory B cells. Exp Cell Res 2018;365:171–176PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Wang X, Dong Q, Li Q, Li Y, Zhao D, Sun J, et al. Dysregulated response of follicular helper T cells to hepatitis B surface antigen promotes HBV persistence in mice and associates with outcomes of patients. Gastroenterology 2018;154:2222–2236PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492–499PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    WHO, W.H. Global hepatitis report 2017. Geneva: World Health Organization; 2017Google Scholar
  84. 84.
    Wieland D, Hofmann M, Thimme R. Overcoming CD8+ T-cell exhaustion in viral hepatitis: lessons from the mouse model and clinical perspectives. Dig Dis Basel Switz 2017;35:334–338CrossRefGoogle Scholar
  85. 85.
    Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA 2004;101:6669–6674PubMedCrossRefGoogle Scholar
  86. 86.
    Xia Y, Stadler D, Lucifora J, Reisinger F, Webb D, Hösel M, et al. Interferon-γ and tumor necrosis factor-α produced by t cells reduce the HBV persistence form, cccDNA, without cytolysis. Gastroenterology 2016;150:194–205PubMedCrossRefGoogle Scholar
  87. 87.
    Xu D-Z, Wang X-Y, Shen X-L, Gong G-Z, Ren H, Guo L-M, et al. Results of a phase III clinical trial with an HBsAg–HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol 2013;59:450–456PubMedCrossRefGoogle Scholar
  88. 88.
    Xu X, Shang Q, Chen X, Nie W, Zou Z, Huang A, et al. Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients. Cell Mol Immunol 2015;12:309–316.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Yip TC, Wong GL, Wong VW, Tse YK, Lui GC, Lam KL, Chan HL. Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients. J Hepatol 2017. CrossRefPubMedGoogle Scholar
  90. 90.
    Yu W-H, Cosgrove C, Berger CT, Cheney PC, Krykbaeva M, Kim AY, et al. ADCC-mediated CD56DIM NK cell responses are associated with early HBsAg clearance in acute HBV infection. Pathog Immun 2018;3:2–18PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  • Julia Lang
    • 1
  • Christoph Neumann-Haefelin
    • 1
  • Robert Thimme
    • 1
  1. 1.Department of Medicine IIUniversity Hospital Freiburg, Faculty of MedicineFreiburgGermany

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