Abstract
Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies.
Key points
-
Unprecedented opportunities exist to develop immunotherapeutic approaches that complement novel antiviral agents to achieve sustained control of residual HBV in chronic HBV infection (CHB).
-
Adaptive immune responses (HBV-specific T cells and B cells) provide precise antiviral targeting of HBV-infected hepatocytes and/or virions, but also have the potential to trigger tissue damage.
-
HBV-specific T cell and B cell responses should be examined in parallel to consider their crosstalk, complementary effector mechanisms and their features of dysfunction in CHB.
-
Inadequate HBV-specific T cell and B cell responses might be restored by immunogenic therapeutic vaccines and might be released from inhibition by antigen load reduction or more specific immunomodulation such as checkpoint inhibition.
-
Alternatively, the failed endogenous adaptive response can be replaced with targeted exogenous T cell- or B cell-derived HBV-specific effectors.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Tassopoulos, N. C. et al. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 92, 1844–1850 (1987).
Cooke, G. S. et al. Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol. Hepatol. 4, 135–184 (2019).
Lazarus, J. V. et al. The hepatitis B epidemic and the urgent need for cure preparedness. Nat. Rev. Gastroenterol. Hepatol. 15, 517–518 (2018).
Revill, P. A. et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol. Hepatol. 4, 545–558 (2019).
Seto, W. K., Lo, Y. R., Pawlotsky, J. M. & Yuen, M. F. Chronic hepatitis B virus infection. Lancet 392, 2313–2324 (2018).
Levrero, M., Subic, M., Villeret, F. & Zoulim, F. Perspectives and limitations for nucleo(t)side analogs in future HBV therapies. Curr. Opin. Virol. 30, 80–89 (2018).
Xia, Y. & Liang, T. J. Development of direct-acting antiviral and host-targeting agents for treatment of hepatitis B virus infection. Gastroenterology 156, 311–324 (2019).
Brahmania, M., Feld, J., Arif, A. & Janssen, H. L. New therapeutic agents for chronic hepatitis B. Lancet Infect. Dis. 16, e10–e21 (2016).
Ko, C., Michler, T. & Protzer, U. Novel viral and host targets to cure hepatitis B. Curr. Opin. Virol. 24, 38–45 (2017).
Asabe, S. et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J. Virol. 83, 9652–9662 (2009).
Rehermann, B., Ferrari, C., Pasquinelli, C. & Chisari, F. V. 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 (1996).
Lok, A. S., Zoulim, F., Dusheiko, G. & Ghany, M. G. Hepatitis B cure: from discovery to regulatory approval. J. Hepatol. 67, 847–861 (2017).
Mason, W. S. et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant. Gastroenterology 151, 986–998.e4 (2016).
Wooddell, C. I. et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci. Transl Med. 9, eaan0241 (2017).
McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).
Hashimoto, M. et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu. Rev. Med. 69, 301–318 (2018).
Maini, M. K. & Gehring, A. J. The role of innate immunity in the immunopathology and treatment of HBV infection. J. Hepatol. 64, S60–S70 (2016).
Maini, M. K. & Pallett, L. J. Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand. Lancet Gastroenterol. Hepatol. 3, 192–202 (2018).
Suslov, A., Wieland, S. & Menne, S. Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B. Curr. Opin. Virol. 30, 9–17 (2018).
Bertoletti, A. & Ferrari, C. Adaptive immunity in HBV infection. J. Hepatol. 64, S71–S83 (2016).
Shin, E. C., Sung, P. S. & Park, S. H. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat. Rev. Immunol. 16, 509–523 (2016).
Loomba, R. & Liang, T. J. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology 152, 1297–1309 (2017).
Burton, A. R. et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J. Clin. Invest. 128, 4588–4603 (2018).
Neumann-Haefelin, C. & Thimme, R. Entering the spotlight: hepatitis B surface antigen-specific B cells. J. Clin. Invest. 128, 4257–4259 (2018).
Salimzadeh, L. et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J. Clin. Invest. 128, 4573–4587 (2018).
Cannon, J. P., Haire, R. N., Rast, J. P. & Litman, G. W. The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms. Immunol. Rev. 200, 12–22 (2004).
Bertoletti, 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. 180, 933–943 (1994).
Bertoletti, A. et al. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature 369, 407–410 (1994).
Rehermann, B., Pasquinelli, C., Mosier, S. M. & Chisari, F. V. 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 (1995).
Rehermann, B. & Thimme, R. Insights from antiviral therapy into immune responses to hepatitis B and C virus infection. Gastroenterology 156, 369–383 (2018).
Desmond, C. P. 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. 86, 1181–1192 (2012).
Kefalakes, H. et al. Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure. Hepatology 62, 47–56 (2015).
Maini, M. K. et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 117, 1386–1396 (1999).
Webster, G. J. 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. 78, 5707–5719 (2004).
Rivino, L. et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J. Clin. Invest. 128, 668–681 (2018).
Boni, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81, 4215–4225 (2007).
Park, J. J. et al. Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology 150, 684–695.e5 (2016).
Schuch, A. et al. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut 68, 905–915 (2019).
Hoogeveen, R. C. et al. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut 68, 893–904 (2018).
Khakpoor, A. et al. Spatiotemporal differences in presentation of CD8 T cell epitopes during HBV infection. J. Virol. 93, e01457-18 (2019).
Gerlich, W. H. Medical virology of hepatitis B: how it began and where we are now. Virol. J. 10, 239 (2013).
Hoofnagle, J. H., Gerety, R. J. & Barker, L. F. Antibody to hepatitis-B-virus core in man. Lancet 2, 869–873 (1973).
Pignatelli, M. et al. Cytotoxic T-cell responses to the nucleocapsid proteins of HBV in chronic hepatitis. Evidence that antibody modulation may cause protracted infection. J. Hepatol. 4, 15–21 (1987).
Farci, P. et al. B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus-associated acute liver failure. Proc. Natl Acad. Sci. USA 107, 8766–8771 (2010).
Chen, Z. et al. Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure. Proc. Natl Acad. Sci. USA 115, E11369–E11378 (2018).
Yuan, Q. et al. Total hepatitis B core antigen antibody, a quantitative non-invasive marker of hepatitis B virus induced liver disease. PLOS ONE 10, e0130209 (2015).
Yuen, M. F. et al. Hepatitis B virus infection. Nat. Rev. Dis. Primers 4, 18035 (2018).
Beasley, R. P. et al. Hepatitis B immune globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state. Initial report of a randomised double-blind placebo-controlled trial. Lancet 2, 388–393 (1981).
Shouval, D. & Samuel, D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 32, 1189–1195 (2000).
Tian, C. et al. Use of ELISpot assay to study HBs-specific B cell responses in vaccinated and HBV infected humans. Emerg. Microbes Infect. 7, 16 (2018).
Xu, X. et al. Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients. Cell Mol. Immunol. 12, 309–316 (2015).
Guidotti, L. G. & Chisari, F. V. Immunobiology and pathogenesis of viral hepatitis. Annu. Rev. Pathol. 1, 23–61 (2006).
Guidotti, L. G., Isogawa, M. & Chisari, F. V. Host-virus interactions in hepatitis B virus infection. Curr. Opin. Immunol. 36, 61–66 (2015).
Thimme, R. et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77, 68–76 (2003).
Guidotti, L. G. et al. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4, 25–36 (1996).
Hoh, A. 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. 89, 7433–7438 (2015).
Phillips, S. et al. CD8(+) T cell control of hepatitis B virus replication: direct comparison between cytolytic and noncytolytic functions. J. Immunol. 184, 287–295 (2010).
Xia, Y. et al. Interferon-γ and tumor necrosis factor-α produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis. Gastroenterology 150, 194–205 (2016).
Lucifora, J. et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221–1228 (2014).
Koh, S. et al. Nonlytic lymphocytes engineered to express virus-specific T-cell receptors limit HBV infection by activating APOBEC3. Gastroenterology 155, 180–193.e6 (2018).
Corti, D. & Lanzavecchia, A. Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 31, 705–742 (2013).
Hangartner, L., Zinkernagel, R. M. & Hengartner, H. Antiviral antibody responses: the two extremes of a wide spectrum. Nat. Rev. Immunol. 6, 231–243 (2006).
Cerino, A., Bremer, C. M., Glebe, D. & Mondelli, M. U. A human monoclonal antibody against hepatitis B surface antigen with potent neutralizing activity. PLOS ONE 10, e0125704 (2015).
Glebe, D. et al. Pre-s1 antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus. J. Virol. 77, 9511–9521 (2003).
Ni, Y. et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146, 1070–1083 (2014).
Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049 (2012).
Urban, S., Bartenschlager, R., Kubitz, R. & Zoulim, F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 147, 48–64 (2014).
Petersen, J. et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat. Biotechnol. 26, 335–341 (2008).
Tu, T. & Urban, S. Virus entry and its inhibition to prevent and treat hepatitis B and hepatitis D virus infections. Curr. Opin. Virol. 30, 68–79 (2018).
Sureau, C. & Salisse, J. A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 57, 985–994 (2013).
Gerlich, W. H. The enigma of concurrent hepatitis B surface antigen (HBsAg) and antibodies to HBsAg. Clin. Infect. Dis. 44, 1170–1172 (2007).
Madalinski, K., Burczynska, B., Heermann, K. H., Uy, A. & Gerlich, W. H. Analysis of viral proteins in circulating immune complexes from chronic carriers of hepatitis B virus. Clin. Exp. Immunol. 84, 493–500 (1991).
Hessell, A. J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).
Lu, L. L., Suscovich, T. J., Fortune, S. M. & Alter, G. Beyond binding: antibody effector functions in infectious diseases. Nat. Rev. Immunol. 18, 46–61 (2018).
Chu, C. M. & Liaw, Y. F. Intrahepatic distribution of hepatitis B surface and core antigens in chronic hepatitis B virus infection. Hepatocyte with cytoplasmic/membranous hepatitis B core antigen as a possible target for immune hepatocytolysis. Gastroenterology 92, 220–225 (1987).
Ray, M. B. et al. Distribution patterns of hepatitis B surface antigen (HBsAg) in the liver of hepatitis patients. J. Clin. Pathol. 29, 94–100 (1976).
Neumann, A. U. et al. Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells. Hepatology 52, 875–885 (2010).
Schilling, R. et al. Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions. J. Virol. 77, 8882–8892 (2003).
Bournazos, S. & Ravetch, J. V. Fcγ receptor function and the design of vaccination strategies. Immunity 47, 224–233 (2017).
Liu, H. et al. Immuno-potentiating pathway of HBsAg-HBIG immunogenic complex visualized. Hum. Vaccin. Immunother. 12, 77–84 (2016).
Shen, P. & Fillatreau, S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 15, 441–451 (2015).
Duddy, M. E., Alter, A. & Bar-Or, A. Distinct profiles of human B cell effector cytokines: a role in immune regulation? J. Immunol. 172, 3422–3427 (2004).
Bouezzedine, F., Fardel, O. & Gripon, P. Interleukin 6 inhibits HBV entry through NTCP down regulation. Virology 481, 34–42 (2015).
Hosel, M. et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50, 1773–1782 (2009).
Palumbo, G. A. et al. IL6 inhibits HBV transcription by targeting the epigenetic control of the nuclear cccDNA minichromosome. PLOS ONE 10, e0142599 (2015).
Karnowski, A. et al. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J. Exp. Med. 209, 2049–2064 (2012).
Harker, J. A., Lewis, G. M., Mack, L. & Zuniga, E. I. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334, 825–829 (2011).
Crotty, S. A brief history of T cell help to B cells. Nat. Rev. Immunol. 15, 185–189 (2015).
Milich, D. R. & McLachlan, A. The nucleocapsid of hepatitis B virus is both a T-cell-independent and a T-cell-dependent antigen. Science 234, 1398–1401 (1986).
Penna, A. et al. Long-lasting memory T cell responses following self-limited acute hepatitis B. J. Clin. Invest. 98, 1185–1194 (1996).
Raziorrouh, B. 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 9, e105703 (2014).
Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).
Dusheiko, G. M., Hoofnagle, J. H., Cooksley, W. G., James, S. P. & Jones, E. A. Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers. J. Clin. Invest. 71, 1104–1113 (1983).
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. 365, 171–176 (2018).
Wang, X. 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 154, 2222–2236 (2018).
Wu, X. et al. Increased circulating follicular regulatory T-like cells may play a critical role in chronic hepatitis B virus infection and disease progression. Viral Immunol. 31, 379–388 (2018).
Milich, D. R. et al. Role of B cells in antigen presentation of the hepatitis B core. Proc. Natl Acad. Sci. USA 94, 14648–14653 (1997).
Whitacre, D. C., Lee, B. O. & Milich, D. R. Use of hepadnavirus core proteins as vaccine platforms. Expert. Rev. Vaccines 8, 1565–1573 (2009).
Lazdina, U. et al. Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent. J. Gen. Virol. 84, 139–146 (2003).
Barnaba, V., Franco, A., Alberti, A., Benvenuto, R. & Balsano, F. Selective killing of hepatitis B envelope antigen-specific B cells by class I-restricted, exogenous antigen-specific T lymphocytes. Nature 345, 258–260 (1990).
Das, A. et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J. Immunol. 189, 3925–3935 (2012).
Hawke, S., Stevenson, P. G., Freeman, S. & Bangham, C. R. Long-term persistence of activated cytotoxic T lymphocytes after viral infection of the central nervous system. J. Exp. Med. 187, 1575–1582 (1998).
Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).
Rosato, P. C., Beura, L. K. & Masopust, D. Tissue resident memory T cells and viral immunity. Curr. Opin. Virol. 22, 44–50 (2017).
Pallett, L. J. et al. IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection. J. Exp. Med. 214, 1567–1580 (2017).
Maini, M. K. et al. 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 (2000).
Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004).
Murakami, J. et al. Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C. Hepatology 30, 143–150 (1999).
Adachi, Y. et al. Distinct germinal center selection at local sites shapes memory B cell response to viral escape. J. Exp. Med. 212, 1709–1723 (2015).
Lefkowitch, J. H. et al. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group. Gastroenterology 104, 595–603 (1993).
Li, L. 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. 68, 912–921 (2018).
Gill, U. S., Pallett, L. J., Kennedy, P. T. F. & Maini, M. K. Liver sampling: a vital window into HBV pathogenesis on the path to functional cure. Gut 67, 767–775 (2018).
Gill, U. S. et al. Fine needle aspirates comprehensively sample intrahepatic immunity. Gut 68, 1493–1503 (2018).
Maini, M. K. & Bertoletti, A. How can the cellular immune response control hepatitis B virus replication? J. Viral Hepat. 7, 321–326 (2000).
Bertoletti, A. & Maini, M. K. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr. Opin. Immunol. 12, 403–408 (2000).
Allweiss, L. et al. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo. Gut 67, 542–552 (2018).
Zong, L. et al. Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice. Nat. Commun. 10, 221 (2019).
Lim, S. G., Agcaoili, J., De Souza, N. N. A. & Chan, E. Therapeutic vaccination for chronic hepatitis B: a systematic review and meta-analysis. J. Viral Hepat. 26, 803–817 (2019).
Michel, M. L., Deng, Q. & Mancini-Bourgine, M. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges. J. Hepatol. 54, 1286–1296 (2011).
Dembek, C., Protzer, U. & Roggendorf, M. Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination. Curr. Opin. Virol. 30, 58–67 (2018).
Kosinska, A. D., Bauer, T. & Protzer, U. Therapeutic vaccination for chronic hepatitis B. Curr. Opin. Virol. 23, 75–81 (2017).
Ha, S. J. et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J. Exp. Med. 205, 543–555 (2008).
Liu, J. et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLOS Pathog. 10, e1003856 (2014).
Fisicaro, P. et al. Anti-viral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 138, 682–693 (2010).
Isogawa, M., Furuichi, Y. & Chisari, F. V. Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity 23, 53–63 (2005).
Iwai, Y., Terawaki, S., Ikegawa, M., Okazaki, T. & Honjo, T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med. 198, 39–50 (2003).
El-Khoueiry, A. B. 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 389, 2492–2502 (2017).
Gane, E. et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J. Hepatol. https://doi.org/10.1016/j.jhep.2019.06.028 (2019).
Bengsch, B. et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity 48, 1029–1045.e5 (2018).
Utzschneider, D. T. et al. Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1. Cell Rep. 22, 3454–3467 (2018).
Utzschneider, D. T. et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 14, 603–610 (2013).
Wieland, D. et al. TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun. 8, 15050 (2017).
Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).
Otano, I. et al. Molecular recalibration of PD-1+ antigen-specific T cells from blood and liver. Mol. Ther. 26, 2553–2566 (2018).
Odorizzi, P. M., Pauken, K. E., Paley, M. A., Sharpe, A. & Wherry, E. J. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J. Exp. Med. 212, 1125–1137 (2015).
Nebbia, G. et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLOS ONE 7, e47648 (2012).
Schurich, A. et al. Role of the co-inhibitory receptor CTLA-4 on apoptosis-prone CD8 T cells in persistent HBV infection. Hepatology 53, 1494–1503 (2011).
Inarrairaegui, M., Melero, I. & Sangro, B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin. Cancer Res. 24, 1518–1524 (2018).
Titanji, K. et al. Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques. J. Clin. Invest. 120, 3878–3890 (2010).
Barnett, B. E. et al. Cutting edge: B cell-intrinsic T-bet expression is required to control chronic viral infection. J. Immunol. 197, 1017–1022 (2016).
Knox, J. J. et al. T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response. JCI Insight 2, 92943 (2017).
Rubtsova, K., Rubtsov, A. V., van Dyk, L. F., Kappler, J. W. & Marrack, P. T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc. Natl Acad. Sci. USA 110, E3216–E3224 (2013).
Naradikian, M. S., Hao, Y. & Cancro, M. P. Age-associated B cells: key mediators of both protective and autoreactive humoral responses. Immunol. Rev. 269, 118–129 (2016).
Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018).
Micco, L. et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J. Hepatol. 58, 225–233 (2013).
Penna, A. et al. Peginterferon-alpha does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis. J. Hepatol. 56, 1239–1246 (2012).
Schurich, A. et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLOS Pathog. 9, e1003208 (2013).
Schurich, A. et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep. 16, 1243–1252 (2016).
Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).
Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity 45, 358–373 (2016).
Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 701–703 (2016).
Lasek, W., Zagozdzon, R. & Jakobisiak, M. Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol. Immunother. 63, 419–435 (2014).
Dunn, C. et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J. Exp. Med. 204, 667–680 (2007).
Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat. Med. 19, 859–868 (2013).
Waggoner, S. N., Cornberg, M., Selin, L. K. & Welsh, R. M. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481, 394–398 (2012).
Waggoner, S. N. et al. Roles of natural killer cells in antiviral immunity. Curr. Opin. Virol. 16, 15–23 (2015).
Peppa, D. et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J. Exp. Med. 210, 99–114 (2013).
Huang, W. C. et al. T cells infiltrating diseased liver express ligands for the NKG2D stress surveillance system. J. Immunol. 198, 1172–1182 (2017).
Boni, C. et al. Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B. Hepatology 62, 1697–1709 (2015).
Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 (2018).
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Attanasio, J. & Wherry, E. J. Costimulatory and coinhibitory receptor pathways in infectious disease. Immunity 44, 1052–1068 (2016).
Fisicaro, P., Boni, C., Barili, V., Laccabue, D. & Ferrari, C. Strategies to overcome HBV-specific T cell exhaustion: checkpoint inhibitors and metabolic re-programming. Curr. Opin. Virol. 30, 1–8 (2018).
Kelly, P. N. CD28 is a critical target for PD-1 blockade. Science 355, 1386 (2017).
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. 61, 1212–1219 (2014).
Menk, A. V. et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp. Med. 215, 1091–1100 (2018).
Pallett, L. J. et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat. Med. 21, 591–600 (2015).
Sandalova, E. et al. Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. Gastroenterology 143, 78–87.e3 (2012).
Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842.e13 (2016).
Kardava, L. et al. Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors. J. Clin. Invest. 121, 2614–2624 (2011).
Boni, C. 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 154, 1764–1777 e1767 (2018).
Janssen, H. L. A. et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J. Hepatol. 68, 431–440 (2018).
Davidson, S., Maini, M. K. & Wack, A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J. Interferon Cytokine Res. 35, 252–264 (2015).
Kurktschiev, P. D. 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. 211, 2047–2059 (2014).
Mueller, S. N. & Ahmed, R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 106, 8623–8628 (2009).
Portugal, S., Obeng-Adjei, N., Moir, S., Crompton, P. D. & Pierce, S. K. Atypical memory B cells in human chronic infectious diseases: an interim report. Cell. Immunol. 321, 18–25 (2017).
Hofmann, M., Wieland, D., Pircher, H. & Thimme, R. Memory vs memory-like: the different facets of CD8(+) T-cell memory in HCV infection. Immunol. Rev. 283, 232–237 (2018).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Wieland, D., Hofmann, M. & Thimme, R. Overcoming CD8+ T-cell exhaustion in viral hepatitis: lessons from the mouse model and clinical perspectives. Dig. Dis. 35, 334–338 (2017).
Bazinet, M. et al. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 2, 877–889 (2017).
Moreno-Cubero, E. et al. Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients? World J. Gastroenterol. 24, 1825–1838 (2018).
Rinker, F. et al. Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J. Hepatol. 69, 584–593 (2018).
Berg, T. et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients – FINITE study. J. Hepatol. 67, 918–924 (2017).
Bertoletti, A. & Rivino, L. Hepatitis B: future curative strategies. Curr. Opin. Infect. Dis. 27, 528–534 (2014).
Gehring, A. & Protzer, U. Targeting innate and adaptive immune responses to cure chronic HBV infection. Gastroenterology 156, 325–337 (2018).
Bohne, F. et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology 134, 239–247 (2008).
Krebs, K. et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 145, 456–465 (2013).
Gehring, A. J. et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J. Hepatol. 55, 103–110 (2011).
Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).
Qasim, W. et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J. Hepatol. 62, 486–491 (2015).
Tan, A. T. et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology 156, 1862–1876.e9 (2019).
Kah, J. et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J. Clin. Invest. 127, 3177–3188 (2017).
Wisskirchen, K. et al. T cell receptor grafting allows virological control of hepatitis B virus infection. J. Clin. Invest. 130 (2019).
Legut, M., Dolton, G., Mian, A. A., Ottmann, O. G. & Sewell, A. K. CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. Blood 131, 311–322 (2018).
Koh, S. et al. A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. Mol. Ther. Nucleic Acids 2, e114 (2013).
Oates, J., Hassan, N. J. & Jakobsen, B. K. ImmTACs for targeted cancer therapy: why, what, how, and which. Mol. Immunol. 67, 67–74 (2015).
Yang, H. et al. Elimination of latently HIV-infected cells from antiretroviral therapy-suppressed subjects by engineered immune-mobilizing T-cell receptors. Mol. Ther. 24, 1913–1925 (2016).
Jo, J. et al. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLOS Pathog 10, e1004210 (2014).
Caskey, M., Klein, F. & Nussenzweig, M. C. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic. Nat. Med. 25, 547–553 (2019).
Bar-On, Y. et al. Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat. Med. 24, 1701–1707 (2018).
Mendoza, P. et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479–484 (2018).
Eren, R. et al. Preclinical evaluation of two human anti-hepatitis B virus (HBV) monoclonal antibodies in the HBV-trimera mouse model and in HBV chronic carrier chimpanzees. Hepatology 32, 588–596 (2000).
Galun, E. et al. Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: safety and antiviral properties. Hepatology 35, 673–679 (2002).
Golsaz-Shirazi, F. et al. Construction of a hepatitis B virus neutralizing chimeric monoclonal antibody recognizing escape mutants of the viral surface antigen (HBsAg). Antivir. Res. 144, 153–163 (2017).
Kucinskaite-Kodze, I. et al. New broadly reactive neutralizing antibodies against hepatitis B virus surface antigen. Virus Res. 211, 209–221 (2016).
Zhang, T. Y. et al. Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen. Gut 65, 658–671 (2016).
Li, D. et al. A potent human neutralizing antibody Fc-dependently reduces established HBV infections. eLife 6, e26738 (2017).
Oliviero, B. et al. Hepatitis C virus-induced NK cell activation causes metzincin-mediated CD16 cleavage and impaired antibody-dependent cytotoxicity. J. Hepatol. 66, 1130–1137 (2017).
Kruse, R. L. et al. In situ liver expression of HBsAg/CD3-bispecific antibodies for HBV Immunotherapy. Mol. Ther. Methods Clin. Dev. 7, 32–41 (2017).
Acknowledgements
M.K.M.’s laboratory is supported by funding from the Wellcome Trust, Cancer Research UK, Medical Research Foundation and the National Institute for Health Research. A.R.B. was funded by a F. Hoffmann-La Roche–University College London joint Impact Studentship.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
M.K.M. receives collaborative research funding from Gilead Sciences and Immunocore and has served as a consultant or on advisory boards for Arbutus Biopharma, F. Hoffmann-La Roche, Gilead Sciences, Immunocore and Janssen.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Gastroenterology & Hepatology thanks U. Protzer and the other anonymous reviewer for their contribution to the peer review of this work.
Rights and permissions
About this article
Cite this article
Maini, M.K., Burton, A.R. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat Rev Gastroenterol Hepatol 16, 662–675 (2019). https://doi.org/10.1038/s41575-019-0196-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-019-0196-9
This article is cited by
-
A two-pronged strategy utilizing exosomes extracted from antigen-presenting cells to combat hepatitis B
Nano Research (2024)
-
A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection
Nature (2024)
-
The scientific basis of combination therapy for chronic hepatitis B functional cure
Nature Reviews Gastroenterology & Hepatology (2023)
-
Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B
Hepatology International (2023)
-
Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers
BMC Immunology (2022)