Top

Current Hepatology Reports

Published in:

Open Access 01-12-2020 | Hepatitis B | Hepatitis B (JK Lim, Section Editor)

Role of Immunomodulators in Functional Cure Strategies for HBV

Authors: Benedikt Binder, Maike Hofmann, Robert Thimme

Published in: Current Hepatology Reports | Issue 4/2020

Abstract

Purpose of Review

Chronic Hepatitis B Virus (HBV) Infection is a major global health burden. Currently, a curative therapy does not exist; thus, there is an urgent need for new therapeutical options. Viral elimination in the natural course of infection results from a robust and multispecific T and B cell response that, however, is dysfunctional in chronically infected patients. Therefore, immunomodulatory therapies that strengthen the immune responses are an obvious approach trying to control HBV infection. In this review, we summarize the rationale and current options of immunological cure of chronic HBV infection.

Recent Findings

Recently, among others, drugs that stimulate the innate immune system or overcome CD8+ T cell exhaustion by checkpoint blockade, and transfer of HBV-specific engineered CD8+ T cells emerged as promising approaches.

Summary

HBV-specific immunity is responsible for viral control, but also for immunopathogenesis. Thus, the development of immunomodulatory therapies is a difficult process on a thin line between viral control and excessive immunopathology. Some promising agents are under investigation. Nevertheless, further research is indispensable in order to optimally orchestrate immunostimulation.

Organization WH (2019) [Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b

Chen JD, Yang HI, Iloeje UH, You SL, Lu SN, Wang LY, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology. 2010;138(5):1747–54.PubMed

Papatheodoridis GV, Dalekos GN, Yurdaydin C, Buti M, Goulis J, Arends P, et al. Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J Hepatol. 2015;62(2):363–70.PubMed

Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. Hepatology. 2017;66(4):1296–313.PubMedPubMedCentral

Hadziyannis SJ. Natural history of chronic hepatitis B in Euro-Mediterranean and African countries. J Hepatol. 2011;55(1):183–91.PubMed

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(7):3532–40.PubMedPubMedCentral

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(6):1386–96.PubMed

Penna A, Artini M, Cavalli A, Levrero M, Bertoletti A, Pilli M, et al. Long-lasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest. 1996;98(5):1185–94.PubMedPubMedCentral

Evens AM, Jovanovic BD, Su YC, 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(5):1170–80.PubMed

10.

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(1):68–76.PubMedPubMedCentral

11.

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(19):9652–62.PubMedPubMedCentral

12.

Balkow S, Kersten A, Tran TT, 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(18):8781–91.PubMedPubMedCentral

13.

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(5415):825–9.PubMed

14.

Xia Y, Stadler D, Lucifora J, Reisinger F, Webb D, Hosel M, et al. Interferon-gamma and tumor necrosis factor-alpha produced by T cells reduce the HBV persistence form, cccDNA, Without Cytolysis. Gastroenterology. 2016;150(1):194–205.PubMed

15.

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(14):7433–8.PubMedPubMedCentral

16.

Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343(6176):1221–8.PubMedPubMedCentral

17.

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(8):4215–25.PubMedPubMedCentral

18.

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(3):327–36.PubMed

19.

Kurktschiev PD, Raziorrouh B, Schraut W, Backmund M, Wachtler M, Wendtner CM, et al. Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J Exp Med. 2014;211(10):2047–59.PubMedPubMedCentral

20.

Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571(7764):211–8.PubMedPubMedCentral

21.

Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019;571(7764):265–9.PubMed

22.

Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection. Nat Immunol. 2019;20(7):890–901.PubMedPubMedCentral

23.

Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9.PubMed

24.

Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, 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. 2019;68(5):905–15.PubMed

25.

Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano 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(4):963–73 e9.PubMed

26.

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(2):1181–92.PubMedPubMedCentral

27.

Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L, et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest. 2018;128(10):4588–603.PubMedPubMedCentral

28.

Salimzadeh L, Le Bert N, Dutertre CA, Gill US, Newell EW, Frey C, et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest. 2018;128(10):4573–87.PubMedPubMedCentral

29.

Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101(17):6669–74.PubMedPubMedCentral

30.

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(6):1237–45.PubMedPubMedCentral

31.

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(7):1508–17 17 e1–10.PubMedPubMedCentral

32.

Gane EJ, Lim YS, Gordon SC, Visvanathan K, Sicard E, Fedorak RN, et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J Hepatol. 2015;63(2):320–8.PubMed

33.

Janssen HLA, Brunetto MR, Kim YJ, Ferrari C, Massetto B, Nguyen AH, et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J Hepatol. 2018;68(3):431–40.PubMed

34.

Daffis S, Balsitis S, Chamberlain J, Zheng J, Santos R, Rowe W, et al. Toll-like receptor 8 agonist GS-9688 induces sustained efficacy in the woodchuck model of chronic hepatitis B. Hepatology. 2020.

35.

Lucifora J, Bonnin M, Aillot L, Fusil F, Maadadi S, Dimier L, et al. Direct antiviral properties of TLR ligands against HBV replication in immune-competent hepatocytes. Sci Rep. 2018;8(1):5390.PubMedPubMedCentral

36.

Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79(11):7269–72.PubMedPubMedCentral

37.

Luangsay S, Ait-Goughoulte M, Michelet M, Floriot O, Bonnin M, Gruffaz M, et al. Expression and functionality of toll- and RIG-like receptors in HepaRG cells. J Hepatol. 2015;63(5):1077–85.PubMed

38.

Wu J, Lu M, Meng Z, Trippler M, Broering R, Szczeponek A, et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology. 2007;46(6):1769–78.PubMed

39.

Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol. 2010;11(1):63–9.PubMed

40.

Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, et al. 5′-triphosphate RNA is the ligand for RIG-I. Science. 2006;314(5801):994–7.PubMed

41.

Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science. 2006;314(5801):997–1001.PubMed

42.

Suresh M, Korolowicz KE, Balarezo M, Iyer RP, Padmanabhan S, Cleary D, et al. Antiviral efficacy and host immune response induction during sequential treatment with SB 9200 followed by Entecavir in woodchucks. PLoS One. 2017;12(1):e0169631.PubMedPubMedCentral

43.

Ebert G, Poeck H, Lucifora J, Baschuk N, Esser K, Esposito I, et al. 5′ Triphosphorylated small interfering RNAs control replication of hepatitis B virus and induce an interferon response in human liver cells and mice. Gastroenterology. 2011;141(2):696–706 e1-3.PubMed

44.

Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498(7454):380–4.PubMedPubMedCentral

45.

Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498(7454):332–7.PubMedPubMedCentral

46.

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. Hepatology. 2016;64(3):746–59.PubMed

47.

Dansako H, Ueda Y, Okumura N, Satoh S, Sugiyama M, Mizokami M, et al. The cyclic GMP-AMP synthetase-STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly. FEBS J. 2016;283(1):144–56.PubMed

48.

Guo F, Tang L, Shu S, Sehgal M, Sheraz M, Liu B, et al. Activation of stimulator of interferon genes in hepatocytes suppresses the replication of hepatitis B virus. Antimicrob Agents Chemother. 2017;61(10).

49.

He J, Hao R, Liu D, Liu X, Wu S, Guo S, et al. Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway. J Gen Virol. 2016;97(12):3368–78.PubMed

50.

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(6):1212–9.PubMed

51.

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):682–93 93 e1–4.PubMed

52.

Fisicaro P, Valdatta C, Massari M, Loggi E, Ravanetti L, Urbani S, et al. Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology. 2012;143(6):1576–85 e4.PubMed

53.

Ferrando-Martinez S, Huang K, Bennett AS, Sterba P, Yu L, Suzich JA, et al. HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic hepatitis B infection. JHEP Rep. 2019;1(3):170–8.PubMedPubMedCentral

54.

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(1):e1003856.PubMedPubMedCentral

55.

•• Gane E, Verdon DJ, Brooks AE, Gaggar A, Nguyen AH, Subramanian GM, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study. J Hepatol. 2019;71(5):900–7 In this study, two promising drugs were combined in the human setting, therefore providing important information on tolerance and efficacy of these therapies and highlighting the potential of checkpoint inhibitors.PubMed

56.

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. Hepatology. 2011;53(5):1494–503.PubMed

57.

Lee YB, Lee JH, Kim YJ, Yoon JH, Lee HS. The effect of therapeutic vaccination for the treatment of chronic hepatitis B virus infection. J Med Virol. 2015;87(4):575–82.PubMed

58.

Al Mahtab M, Akbar SMF, Aguilar JC, Guillen G, Penton E, Tuero A, et al. Treatment of chronic hepatitis B naive patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS One. 2018;13(8):e0201236.PubMedPubMedCentral

59.

Boni C, Janssen HLA, Rossi M, Yoon SK, Vecchi A, Barili V, et al. Combined GS-4774 and tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis. Gastroenterology. 2019;157(1):227–41 e7.PubMed

60.

Zahn T, Akhras S, Spengler C, Murra RO, Holzhauser T, Hildt E. A new approach for therapeutic vaccination against chronic HBV infections. Vaccine. 2020;38(15):3105–20.PubMed

61.

Ilan Y, Nagler A, Adler R, Naparstek E, Or R, Slavin S, et al. Adoptive transfer of immunity to hepatitis B virus after T cell-depleted allogeneic bone marrow transplantation. Hepatology. 1993;18(2):246–52.PubMed

62.

Ilan Y, Nagler A, Zeira E, Adler R, Slavin S, Shouval D. Maintenance of immune memory to the hepatitis B envelope protein following adoptive transfer of immunity in bone marrow transplant recipients. Bone Marrow Transplant. 2000;26(6):633–8.PubMed

63.

Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kurschner T, Schulze A, et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology. 2008;134(1):239–47.PubMed

64.

Krebs K, Bottinger N, Huang LR, Chmielewski M, Arzberger S, Gasteiger G, et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology. 2013;145(2):456–65.PubMed

65.

• Kruse RL, Shum T, Tashiro H, Barzi M, Yi Z, Whitten-Bauer C, et al. HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice. Cytotherapy. 2018;20(5):697–705 These studies highlight the potential of engineered virus-specific CD8+ T cells to exert antiviral functions in vivo.PubMedPubMedCentral

66.

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(1):180–93 e6.PubMed

67.

Kah J, Koh S, Volz T, Ceccarello E, Allweiss L, Lutgehetmann M, et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J Clin Invest. 2017;127(8):3177–88.PubMedPubMedCentral

68.

Qasim W, Brunetto M, Gehring AJ, Xue SA, Schurich A, Khakpoor A, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol. 2015;62(2):486–91.PubMed

Title: Role of Immunomodulators in Functional Cure Strategies for HBV
Authors: Benedikt Binder
Maike Hofmann
Robert Thimme
Publication date: 01-12-2020
Publisher: Springer US
Keyword: Hepatitis B
Published in: Current Hepatology Reports / Issue 4/2020
Electronic ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-020-00538-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 4/2020

Diagnosis and Management of Occult Hepatitis B Infection

Role of Nucleic Acid Polymers and Entry Inhibitors in Functional Cure Strategies for HBV

Racial and Sex Disparities in Hepatocellular Carcinoma in the USA

Chronic Hepatitis B and HIV Coinfection: a Continuing Challenge in the Era of Antiretroviral Therapy

High-Risk Groups for Non-alcoholic Fatty Liver and Non-alcoholic Steatohepatitis Development and Progression

Medication Non-adherence among Liver Transplant Recipients

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials