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Volume 37 Issue 5
May  2021
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Article Navigation >  Journal of Clinical Hepatology  > 2021  >  37(5): 1016-1021

Strategies and advances in targeting adaptive immunity to cure chronic hepatitis B

DOI: 10.3969/j.issn.1001-5256.2021.05.005

  • Center of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

  • Received Date: 2021-03-26
  • Accepted Date: 2021-04-14
  • Published Date: 2021-05-20
    Abstract
  • Chronic hepatitis B (CHB) is a major global public health issue, and although direct-acting antiviral agents can control hepatitis B virus (HBV) replication, it is difficult to achieve the cure of CHB. Host adaptive immune response plays a key role in eliminating HBV, and it is expected to achieve the functional cure of CHB by rebuilding the patient's adaptive immunity. Great progress has been made in therapeutic vaccines, cellular immunotherapy, immune checkpoint blockade, T cell metabolic reprogramming, and strategies of neutralizing antibody targeting adaptive immunity for the treatment of hepatitis B. This article summarizes the above-mentioned therapies for hepatitis B in recent years.

     

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  • [1]
    SEEGER C, MASON WS. Molecular biology of hepatitis B virus infection[J]. Virology, 2015, 479-480: 672-686. DOI: 10.1016/j.virol.2015.02.031.
    [2]
    WARD JW, HINMAN AR. What is needed to eliminate hepatitis B virus and hepatitis C virus as global health threats[J]. Gastroenterology, 2019, 156(2): 297-310. DOI: 10.1053/j.gastro.2018.10.048.
    [3]
    XIE Q, NING Q, WANG GQ, et al. Clinical cure strategy for hepatitis B: Immunomodulatory therapy[J]. Chin J Hepatol, 2020, 28(8): 644-648. DOI: 10.3760/cma.j.cn501113-20200722-00410.

    谢青, 宁琴, 王贵强, 等. 乙型肝炎临床治愈策略: 抗病毒药物与免疫调节治疗[J]. 中华肝脏病杂志, 2020, 28(8): 644-648. DOI: 10.3760/cma.j.cn501113-20200722-00410.
    [4]
    BALKOW S, KERSTEN A, TRAN TT, 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]. J Virol, 2001, 75(18): 8781-8791. DOI: 10.1128/jvi.75.18.8781-8791.2001.
    [5]
    FERRARI C. HBV and the immune response[J]. Liver Int, 2015, 35(Suppl 1): 121-128. DOI: 10.1111/liv.12749.
    [6]
    PENNA A, DEL PRETE G, CAVALLI A, et al. Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B[J]. Hepatology, 1997, 25(4): 1022-1027. DOI: 10.1002/hep.510250438.
    [7]
    LANG J, NEUMANN-HAEFELIN C, THIMME R. Immunological cure of HBV infection[J]. Hepatol Int, 2019, 13(2): 113-124. DOI: 10.1007/s12072-018-9912-8.
    [8]
    MENG Z, CHEN Y, LU M. Advances in targeting the innate and adaptive immune systems to cure chronic hepatitis B virus infection[J]. Front Immunol, 2019, 10: 3127. DOI: 10.3389/fimmu.2019.03127.
    [9]
    ZHANG TY, YUAN Q, ZHAO JH, et al. Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen[J]. Gut, 2016, 65(4): 658-671. DOI: 10.1136/gutjnl-2014-308964.
    [10]
    PAUL S, DICKSTEIN A, SAXENA A, et al. Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: A meta-analysis[J]. Hepatology, 2017, 66(2): 379-388. DOI: 10.1002/hep.29082.
    [11]
    EVENS AM, JOVANOVIC BD, SU YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: Meta-analysis and examination of FDA safety reports[J]. Ann Oncol, 2011, 22(5): 1170-1180. DOI: 10.1093/annonc/mdq583.
    [12]
    GINZBERG D, WONG RJ, GISH R. Global HBV burden: Guesstimates and facts[J]. Hepatol Int, 2018, 12(4): 315-329. DOI: 10.1007/s12072-018-9884-8.
    [13]
    KEFALAKES H, BUDEUS B, WALKER A, et al. Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure[J]. Hepatology, 2015, 62(1): 47-56. DOI: 10.1002/hep.27771.
    [14]
    BLOCK TM, MEHTA AS, BLUMBERG BS, et al. Does rapid oligomerization of hepatitis B envelope proteins play a role in resistance to proteasome degradation and enhance chronicity?[J]. DNA Cell Biol, 2006, 25(3): 165-170. DOI: 10.1089/dna.2006.25.165.
    [15]
    ATTANASIO J, WHERRY EJ. Costimulatory and coinhibitory receptor pathways in infectious disease[J]. Immunity, 2016, 44(5): 1052-1068. DOI: 10.1016/j.immuni.2016.04.022.
    [16]
    CROTTY S. Follicular helper CD4 T cells (TFH)[J]. Annu Rev Immunol, 2011, 29: 621-663. DOI: 10.1146/annurev-immunol-031210-101400.
    [17]
    WANG X, DONG Q, LI Q, 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[J]. Gastroenterology, 2018, 154(8): 2222-2236. DOI: 10.1053/j.gastro.2018.03.021.
    [18]
    DU KY, YANG DL, LIU J. Regulatory T cells in hepatitis B[J]. J Prac Hepatol, 2019, 22(5): 613-616. DOI: 10.3969/j.issn.1672- 5069.2019.05.002.

    杜科业, 杨东亮, 刘嘉. 慢性乙型肝炎与调节性T细胞研究进展[J]. 实用肝脏病杂志, 2019, 22(5): 613-616. DOI: 10.3969/j.issn.1672- 5069.2019.05.002.
    [19]
    LI K, LIU H, GUO T. Th17/Treg imbalance is an indicator of liver cirrhosis process and a risk factor for HCC occurrence in HBV patients[J]. Clin Res Hepatol Gastroenterol, 2017, 41(4): 399-407. DOI: 10.1016/j.clinre.2016.12.004.
    [20]
    LIM CJ, LEE YH, PAN L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma[J]. Gut, 2019, 68(5): 916-927. DOI: 10.1136/gutjnl-2018-316510.
    [21]
    OLIVIERO B, CERINO A, VARCHETTA S, et al. Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections[J]. J Hepatol, 2011, 55(1): 53-60. DOI: 10.1016/j.jhep.2010.10.016.
    [22]
    DAS A, ELLIS G, PALLANT C, et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection[J]. J Immunol, 2012, 189(8): 3925-3935. DOI: 10.4049/jimmunol.1103139.
    [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[J]. Clin Sci (Lond), 2016, 130(11): 907-919. DOI: 10.1042/CS20160069.
    [24]
    van der MOLEN RG, SPRENGERS D, BINDA RS, et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B[J]. Hepatology, 2004, 40(3): 738-746. DOI: 10.1002/hep.20366.
    [25]
    WOLTMAN AM, BOONSTRA A, JANSSEN HL. Dendritic cells in chronic viral hepatitis B and C: Victims or guardian angels?[J]. Gut, 2010, 59(1): 115-125. DOI: 10.1136/gut.2009.181040.
    [26]
    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[J]. Gastroenterology, 2010, 138(2): 682-693. DOI: 10.1053/j.gastro.2009.09.052.
    [27]
    OUAGUIA L, LEROY V, DUFEU-DUCHESNE T, et al. Circulating and hepatic BDCA1+, BDCA2+, and BDCA3+ dendritic cells are differentially subverted in patients with chronic HBV infection[J]. Front Immunol, 2019, 10: 112. DOI: 10.3389/fimmu.2019.00112.
    [28]
    LOK AS, PAN CQ, HAN SH, et al. Randomized phase Ⅱ study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B[J]. J Hepatol, 2016, 65(3): 509-516. DOI: 10.1016/j.jhep.2016.05.016.
    [29]
    BONI C, JANSSEN H, ROSSI M, et al. Combined GS-4774 and tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis[J]. Gastroenterology, 2019, 157(1): 227-241. e7. DOI: 10.1053/j.gastro.2019.03.044.
    [30]
    YOON SK, SEO YB, IM SJ, et al. Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice[J]. Liver Int, 2015, 35(3): 805-815. DOI: 10.1111/liv.12530.
    [31]
    MARTIN P, DUBOIS C, JACQUIER E, et al. TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice[J]. Gut, 2015, 64(12): 1961-1971. DOI: 10.1136/gutjnl-2014-308041.
    [32]
    ZOULIM F, FOURNIER C, HABERSETZER F, et al. Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: A phase 1b placebo-controlled trial[J]. Hum Vaccin Immunother, 2020, 16(2): 388-399. DOI: 10.1080/21645515.2019.1651141.
    [33]
    AL MAHTAB M, AKBAR S, AGUILAR JC, et al. Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase Ⅲ clinical trial)[J]. PLoS One, 2018, 13(8): e0201236. DOI: 10.1371/journal.pone.0201236.
    [34]
    LAU GK, LOK AS, LIANG RH, et al. Clearance of hepatitis B surface antigen after bone marrow transplantation: Role of adoptive immunity transfer[J]. Hepatology, 1997, 25(6): 1497-1501. DOI: 10.1002/hep.510250631.
    [35]
    BOHNE F, CHMIELEWSKI M, EBERT G, et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes[J]. Gastroenterology, 2008, 134(1): 239-247. DOI: 10.1053/j.gastro.2007.11.002.
    [36]
    KREBS K, BÖTTINGER N, HUANG LR, et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice[J]. Gastroenterology, 2013, 145(2): 456-465. DOI: 10.1053/j.gastro.2013.04.047.
    [37]
    KRUSE RL, SHUM T, TASHIRO H, et al. HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice[J]. Cytotherapy, 2018, 20(5): 697-705. DOI: 10.1016/j.jcyt.2018.02.002.
    [38]
    KAH J, KOH S, VOLZ T, et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection[J]. J Clin Invest, 2017, 127(8): 3177-3188. DOI: 10.1172/JCI93024.
    [39]
    LIU Q, TIAN Y, LI Y, et al. In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma[J]. J Immunother Cancer, 2020, 8(2): e001748. DOI: 10.1136/jitc-2020-001748.
    [40]
    QASIM W, BRUNETTO M, GEHRING AJ, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient[J]. J Hepatol, 2015, 62(2): 486-491. DOI: 10.1016/j.jhep.2014.10.001.
    [41]
    BERTOLETTI A. ImmTAV, a new immunotherapy targeting the source of HBV infection[J]. Hepatology, 2020, 72(5): 1514-1517. DOI: 10.1002/hep.31527.
    [42]
    FERGUSSON JR, WALLACE Z, CONNOLLY MM, et al. Immune-mobilizing monoclonal T cell receptors mediate specific and rapid elimination of hepatitis B-infected cells[J]. Hepatology, 2020, 72(5): 1528-1540. DOI: 10.1002/hep.31503.
    [43]
    AKBAR SM, CHEN S, AL-MAHTAB M, et al. Strong and multi-antigen specific immunity by hepatitis B core antigen (HBcAg)-based vaccines in a murine model of chronic hepatitis B: HBcAg is a candidate for a therapeutic vaccine against hepatitis B virus[J]. Antiviral Res, 2012, 96(1): 59-64. DOI: 10.1016/j.antiviral.2012.07.011.
    [44]
    SUN HH, ZHOU DF, ZHOU JY. The role of DCs in the immunopathogenesis of chronic HBV infection and the methods of inducing DCs maturation[J]. J Med Virol, 2016, 88(1): 13-20. DOI: 10.1002/jmv.24306.
    [45]
    MA YJ, HE M, HAN JA, et al. A clinical study of HBsAg-activated dendritic cells and cytokine-induced killer cells during the treatment for chronic hepatitis B[J]. Scand J Immunol, 2013, 78(4): 387-393. DOI: 10.1111/sji.12097.
    [46]
    AKBAR SM, FURUKAWA S, HORⅡKE N, et al. Safety and immunogenicity of hepatitis B surface antigen-pulsed dendritic cells in patients with chronic hepatitis B[J]. J Viral Hepat, 2011, 18(6): 408-414. DOI: 10.1111/j.1365-2893.2010.01320.x.
    [47]
    LIU J, ZHANG E, MA Z, et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection[J]. PLoS Pathog, 2014, 10(1): e1003856. DOI: 10.1371/journal.ppat.1003856.
    [48]
    JACOBI FJ, WILD K, SMITS M, et al. OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection[J]. J Hepatol, 2019, 70(6): 1103-1113. DOI: 10.1016/j.jhep.2019.02.016.
    [49]
    KAMPHORST AO, WIELAND A, NASTI T, et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent[J]. Science, 2017, 355(6332): 1423-1427. DOI: 10.1126/science.aaf0683.
    [50]
    WEI SC, LEVINE JH, COGDILL AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade[J]. Cell, 2017, 170(6): 1120-1133. e17. DOI: 10.1016/j.cell.2017.07.024.
    [51]
    HUANG AC, POSTOW MA, ORLOWSKI RJ, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response[J]. Nature, 2017, 545(7652): 60-65. DOI: 10.1038/nature22079.
    [52]
    GANE E, VERDON DJ, BROOKS AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study[J]. J Hepatol, 2019, 71(5): 900-907. DOI: 10.1016/j.jhep.2019.06.028.
    [53]
    BENGSCH B, JOHNSON AL, KURACHI M, et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion[J]. Immunity, 2016, 45(2): 358-373. DOI: 10.1016/j.immuni.2016.07.008.
    [54]
    FISICARO P, BONI C, BARILI V, et al. Strategies to overcome HBV-specific T cell exhaustion: Checkpoint inhibitors and metabolic re-programming[J]. Curr Opin Virol, 2018, 30: 1-8. DOI: 10.1016/j.coviro.2018.01.003.
    [55]
    FISICARO P, BARILI V, MONTANINI B, et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B[J]. Nat Med, 2017, 23(3): 327-336. DOI: 10.1038/nm.4275.
    [56]
    ACERBI G, MONTALI I, FERRIGNO GD, et al. Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B[J]. J Hepatol, 2021, 74(4): 783-793. DOI: 10.1016/j.jhep.2020.10.034.
    [57]
    GAO Y, ZHANG TY, YUAN Q, et al. Antibody-mediated immunotherapy against chronic hepatitis B virus infection[J]. Hum Vaccin Immunother, 2017, 13(8): 1768-1773. DOI: 10.1080/21645515.2017.1319021.
    [58]
    Initial data from ongoing phase 1 trial of VIR-3434 for chronic hepatitis B virus infection demonstrates significant and rapid reduction in hepatitis B surface antigen[EB/OL]. (2021-1-26)[2021-3-26].https://investors.vir.bio/news-releases/news-release-details/initial-data-ongoing-phase-1-trial-vir-3434-chronic-hepatitis-b.
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