A global scientific strategy to cure hepatitis B

The Lancet Gastroenterology & Hepatology - Tập 4 Số 7 - Trang 545-558 - 2019
Peter Revill1,2, Francis V. Chisari3, Joan M. Block4, Maura Dandri5,6, Adam J. Gehring7, Haitao Guo8, Jianming Hu9, Anna Kramvis10, Pietro Lampertico11, Harry L.A. Janssen12, Massimo Levrero13,14,15,16,17, Wenhui Li18,19, T. Jake Liang20, Seng Gee Lim21, Fengmin Lu22, Capucine Pénicaud1, John E. Tavis23, Robert Thimme24, Fabien Zoulim15,16, Patrick Arbuthnot, André Boonstra, Kyong‐Mi Chang, Per-Jei Chen, Dieter Glebe, Luca G. Guidotti, Jacques Fellay, Carlo Ferrari, Louis Jansen, Daryl Lau, Anna S. Lok, Mala K. Maini, William Mason, Gail Matthews, Dimitrios Paraskevis, Jörg Petersen, Barbara Rehermann, Eui‐Cheol Shin, A. Thompson, Florian van Bömmel, Fusheng Wang, Koichi Watashi, Hung‐Chih Yang, Zhenghong Yuan, Man‐Fung Yuen, Timothy M. Block4, Veronica Miller, Ulrike Protzer, Christian Bréchot, Stephen Locarnini, Marion G. Peters, Raymond F. Schinazi
1Peter Doherty Institute of Infection and Immunity, Melbourne, Australia
2Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Melbourne, Australia
3Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA, USA
4Hepatitis B Foundation, Doylestown, PA, USA
5German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel partner site, Hamburg, Germany
6I Medical Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
7Toronto General Hospital Research Institute, Department of Immunology, University of Toronto, Canada
8Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
9Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, USA
10Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa
11CRC “A. M. and A. Migliavacca” Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
12Toronto Centre for Liver Disease, University of Toronto, Canada
13, Istituto Italiano di Tecnologia (IIT), Rome, Italy
14Department of Internal Medicine - DMISM, Sapienza University, Rome, Italy
15Hepatology Department, Hospices Civils de Lyon, Lyon, France
16INSERM Unit 1052, Cancer Research Center of Lyon, Lyon, France
17[email protected]
18National Institute of Biological Sciences, Beijing, China
19Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
20National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
21Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore
22Peking University Health Science Center, Beijing, China
23Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, MI, USA
24Department of Medicine II, Medical Center, University of Freiburg; Freiburg, Germany

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Tài liệu tham khảo

Stanaway, 2016, The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013, Lancet, 388, 1081, 10.1016/S0140-6736(16)30579-7

Chisari, 1995, Hepatitis B virus immunopathogenesis, Annu Rev Immunol, 13, 29, 10.1146/annurev.iy.13.040195.000333

Grossi, 2017, Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs), Liver Int, 37, 45, 10.1111/liv.13291

O'Hara, 2017, Hepatitis B virus infection as a neglected tropical disease, PLoS Negl Trop Dis, 11, e0005842, 10.1371/journal.pntd.0005842

Revill, 2016, Global strategies are required to cure and eliminate HBV infection, Nat Rev Gastroenterol Hepatol, 13, 239, 10.1038/nrgastro.2016.7

Yan, 2012, Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus, eLife, 1, e00049, 10.7554/eLife.00049

Nassal, 2015, HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B, Gut, 64, 1972, 10.1136/gutjnl-2015-309809

Newbold, 1995, The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes, J Virol, 69, 3350, 10.1128/JVI.69.6.3350-3357.1995

Bock, 2001, Structural organization of the hepatitis B virus minichromosome, J Mol Biol, 307, 183, 10.1006/jmbi.2000.4481

Messageot, 2003, Proteolytic processing of the hepatitis B virus e antigen precursor. Cleavage at two furin consensus sequences, J Biol Chem, 278, 891, 10.1074/jbc.M207634200

2017, EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection, J Hepatol, 67, 370, 10.1016/j.jhep.2017.03.021

Michalak, 1994, Hepatitis B virus persistence after recovery from acute viral hepatitis, J Clin Invest, 93, 230, 10.1172/JCI116950

Rehermann, 1996, 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, 10.1038/nm1096-1104

Werle-Lapostolle, 2004, Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy, Gastroenterology, 126, 1750, 10.1053/j.gastro.2004.03.018

Seetharam, 2014, Immunosuppression in patients with chronic hepatitis B, Curr Hepatol Rep, 13, 235, 10.1007/s11901-014-0238-2

2018, Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study, Lancet Gastroenterol Hepatol, 3, 383, 10.1016/S2468-1253(18)30056-6

2016

Lazarus, 2018, The hepatitis B epidemic and the urgent need for cure preparedness, Nat Rev Gastroenterol Hepatol, 15, 517, 10.1038/s41575-018-0041-6

Nayagam, 2016, Requirements for global elimination of hepatitis B: a modelling study, Lancet Infect Dis, 16, 1399, 10.1016/S1473-3099(16)30204-3

Zoulim, 2009, Hepatitis B virus resistance to nucleos(t)ide analogues, Gastroenterology, 137, 1593, 10.1053/j.gastro.2009.08.063

Belloni, 2012, IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome, J Clin Invest, 122, 529, 10.1172/JCI58847

Wieland, 2005, Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids, Proc Natl Acad Sci USA, 102, 9913, 10.1073/pnas.0504273102

Gill, 2016, Interferon alpha induces sustained changes in NK cell responsiveness to hepatitis B viral load suppression in vivo, PLoS Pathog, 12, e1005788, 10.1371/journal.ppat.1005788

Maini, 2016, The role of innate immunity in the immunopathology and treatment of HBV infection, J Hepatol, 64, S60, 10.1016/j.jhep.2016.01.028

Maini, 2013, NK cells: a double-edged sword in chronic hepatitis B virus infection, Front Immunol, 4, 57, 10.3389/fimmu.2013.00057

Kramvis, 2014, Genotypes and genetic variability of hepatitis B virus, Intervirology, 57, 141, 10.1159/000360947

Chen, 2007, Long-term outcomes in hepatitis B: the REVEAL-HBV study, Clin Liver Dis, 11, 797, 10.1016/j.cld.2007.08.005

Yuen, 2008, HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma, Gastroenterology, 135, 1192, 10.1053/j.gastro.2008.07.008

Lok, 2017, Hepatitis B cure: from discovery to regulatory approval, Hepatology, 66, 1296, 10.1002/hep.29323

Zeisel, 2015, Towards an HBV cure: state-of-the-art and unresolved questions—report of the ANRS workshop on HBV cure, Gut, 64, 1314, 10.1136/gutjnl-2014-308943

Thimme, 2003, CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection, J Virol, 77, 68, 10.1128/JVI.77.1.68-76.2003

Guidotti, 1999, Viral clearance without destruction of infected cells during acute HBV infection, Science, 284, 825, 10.1126/science.284.5415.825

Rehermann, 2003, Immune responses in hepatitis B virus infection, Semin Liver Dis, 23, 21, 10.1055/s-2003-37586

Hosaka, 2013, Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection, Hepatology, 58, 98, 10.1002/hep.26180

Papatheodoridis, 2017, The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B, Hepatology, 66, 1444, 10.1002/hep.29320

Sugarman, 2017, Ethics and hepatitis B cure research, Gut, 66, 389, 10.1136/gutjnl-2016-313009

Levrero, 2016, HBV cure: why, how, when?, Curr Opin Virol, 18, 135, 10.1016/j.coviro.2016.06.003

Blumberg, 1965, A “new” antigen in leukemia sera, JAMA, 191, 541, 10.1001/jama.1965.03080070025007

Strick-Marchand, 2015, A novel mouse model for stable engraftment of a human immune system and human hepatocytes, PLoS One, 10, e0119820, 10.1371/journal.pone.0119820

Kah, 2017, Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection, J Clin Invest, 127, 3177, 10.1172/JCI93024

Klumpp, 2018, Efficacy of NVR 3-778, alone and in combination with pegylated interferon, vs entecavir in uPA/SCID mice with humanized livers and HBV infection, Gastroenterology, 154, 652, 10.1053/j.gastro.2017.10.017

Lucifora, 2014, Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA, Science, 343, 1221, 10.1126/science.1243462

Wu, 2018, Establishment of cre-mediated HBV recombinant cccDNA (rcccDNA) cell line for cccDNA biology and antiviral screening assays, Antiviral Res, 152, 45, 10.1016/j.antiviral.2018.02.007

Xia, 2016, Interferon-gamma and tumor necrosis factor-alpha produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis, Gastroenterology, 150, 194, 10.1053/j.gastro.2015.09.026

Chisari, 2014, Comment on “Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA”, Science, 344, 1237, 10.1126/science.1254082

Xia, 2014, Response to Comment on “Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA”, Science, 344, 1237, 10.1126/science.1254083

Seeger, 2016, Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA, Mol Ther, 24, 1258, 10.1038/mt.2016.94

Bloom, 2017, A T7 endonuclease I assay to detect talen-mediated targeted mutation of HBV cccDNA, Methods Mol Biol, 1540, 85, 10.1007/978-1-4939-6700-1_8

Yang, 2014, Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance, Emerg Microbes Infect, 3, e64, 10.1038/emi.2014.64

Belloni, 2009, Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function, Proc Natl Acad Sci USA, 106, 19975, 10.1073/pnas.0908365106

Levrero, 2009, Control of cccDNA function in hepatitis B virus infection, J Hepatol, 51, 581, 10.1016/j.jhep.2009.05.022

Lucifora, 2011, Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection, J Hepatol, 55, 996, 10.1016/j.jhep.2011.02.015

Pollicino, 2006, Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones, Gastroenterology, 130, 823, 10.1053/j.gastro.2006.01.001

Guo, 2011, HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state, Epigenetics, 6, 720, 10.4161/epi.6.6.15815

Decorsiere, 2016, Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor, Nature, 531, 386, 10.1038/nature17170

Livingston, 2017, Identifying and characterizing interplay between hepatitis B virus X protein and Smc5/6, Viruses, 9, E69, 10.3390/v9040069

Murphy, 2016, Hepatitis B virus X protein promotes degradation of SMC5/6 to enhance HBV replication, Cell Rep, 16, 2846, 10.1016/j.celrep.2016.08.026

Wooddell, 2017, 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, 10.1126/scitranslmed.aan0241

Maepa, 2017, Sustained inhibition of HBV replication in vivo after systemic injection of AAVs encoding artificial antiviral primary microRNAs, Mol Ther Nucleic Acids, 7, 190, 10.1016/j.omtn.2017.04.007

Zhang, 2016, In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection, J Clin Invest, 126, 1079, 10.1172/JCI83339

Li, 2018, Distribution of hepatitis B virus nuclear DNA, J Virol, 92, e01391

Cai, 2016, Establishment of an inducible HBV stable cell line that expresses cccDNA-dependent epitope-tagged HBeAg for screening of cccDNA modulators, Antiviral Res, 132, 26, 10.1016/j.antiviral.2016.05.005

Guo, 2015, Metabolism and function of hepatitis B virus cccDNA: implications for the development of cccDNA-targeting antiviral therapeutics, Antiviral Res, 122, 91, 10.1016/j.antiviral.2015.08.005

Li, 2016, Minicircle HBV cccDNA with a Gaussia luciferase reporter for investigating HBV cccDNA biology and developing cccDNA-targeting drugs, Sci Rep, 6, 36483, 10.1038/srep36483

Thomas, 2016, Experimental models of hepatitis B and C- new insights and progress, Nat Rev Gastroenterol Hepatol, 13, 362, 10.1038/nrgastro.2016.37

Xia, 2017, Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions, J Hepatol, 66, 494, 10.1016/j.jhep.2016.10.009

Kaneko, 2016, Human induced pluripotent stem cell-derived hepatic cell lines as a new model for host interaction with hepatitis B virus, Sci Rep, 6, 29358, 10.1038/srep29358

Sakurai, 2017, Human induced-pluripotent stem cell-derived hepatocyte-like cells as an in vitro model of human hepatitis B virus infection, Sci Rep, 7, 45698, 10.1038/srep45698

Ortega-Prieto, 2018, 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection, Nat Commun, 9, 682, 10.1038/s41467-018-02969-8

Allweiss, 2018, Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo, Gut, 67, 542, 10.1136/gutjnl-2016-312162

Dusseaux, 2017, Viral load affects the immune response to HBV in mice with humanized immune system and liver, Gastroenterology, 153, 1647, 10.1053/j.gastro.2017.08.034

Cui, 2015, Hepatitis B virus covalently closed circular DNA formation in immortalized mouse hepatocytes associated with nucleocapsid destabilization, J Virol, 89, 9021, 10.1128/JVI.01261-15

Glebe, 2003, Pre-s1 antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus, J Virol, 77, 9511, 10.1128/JVI.77.17.9511-9521.2003

Walter, 1996, Hepatitis B virus infection of tupaia hepatocytes in vitro and in vivo, Hepatology, 24, 1

Burwitz, 2017, Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques, Nat Commun, 8, 2146, 10.1038/s41467-017-01953-y

Clements, 2011, A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system, Curr Opin HIV AIDS, 6, 37, 10.1097/COH.0b013e3283412413

Allweiss, 2017, The role of cccDNA in HBV maintenance, Viruses, 9, E156, 10.3390/v9060156

Hu, 2017, Complete and incomplete hepatitis B virus particles: formation, function and application, Viruses, 9, 10.3390/v9030056

Giersch, 2017, Serum HBV pgRNA as a clinical marker for cccDNA activity, J Hepatol, 66, 460, 10.1016/j.jhep.2016.09.028

van Bommel, 2015, Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors, Hepatology, 61, 66, 10.1002/hep.27381

Wang, 2016, Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound, J Hepatol, 65, 700, 10.1016/j.jhep.2016.05.029

Asabe, 2009, The size of the viral inoculum contributes to the outcome of hepatitis B virus infection, J Virol, 83, 9652, 10.1128/JVI.00867-09

Ebert, 2011, 5′ triphosphorylated small interfering RNAs control replication of hepatitis B virus and induce an interferon response in human liver cells and mice, Gastroenterology, 141, 696, 10.1053/j.gastro.2011.05.001

Isogawa, 2005, Toll-like receptor signaling inhibits hepatitis B virus replication in vivo, J Virol, 79, 7269, 10.1128/JVI.79.11.7269-7272.2005

Janssen, 2018, Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B, J Hepatol, 68, 431, 10.1016/j.jhep.2017.10.027

Suresh, 2017, Antiviral efficacy and host immune response induction during sequential treatment with SB 9200 followed by entecavir in woodchucks, PLoS One, 12, e0169631, 10.1371/journal.pone.0169631

Bengsch, 2014, 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, 10.1016/j.jhep.2014.07.005

Boni, 2007, Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection, J Virol, 81, 4215, 10.1128/JVI.02844-06

Fisicaro, 2010, Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B, Gastroenterology, 138, 682, 10.1053/j.gastro.2009.09.052

Nebbia, 2012, Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection, PLoS One, 7, e47648, 10.1371/journal.pone.0047648

Schurich, 2011, Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-prone CD8 T cells in persistent hepatitis B virus infection, Hepatology, 53, 1494, 10.1002/hep.24249

Isogawa, 2013, CD40 activation rescues antiviral CD8(+) T cells from PD-1-mediated exhaustion, PLoS Pathog, 9, e1003490, 10.1371/journal.ppat.1003490

Maier, 2007, PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver, J Immunol, 178, 2714, 10.4049/jimmunol.178.5.2714

Schurich, 2013, The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells, PLoS Pathog, 9, e1003208, 10.1371/journal.ppat.1003208

Gehring, 2017, New treatments to reach functional cure: rationale and challenges for emerging immune-based therapies, Best Pract Res Clin Gastroenterol, 31, 337, 10.1016/j.bpg.2017.05.004

Pallett, 2017, IL-2(high) tissue-resident T cells in the human liver: sentinels for hepatotropic infection, J Exp Med, 214, 1567, 10.1084/jem.20162115

Stegmann, 2016, CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver, Sci Rep, 6, 26157, 10.1038/srep26157

Boeijen, 2017, Hepatitis B virus infection and the immune response: the big questions, Best Pract Res Clin Gastroenterol, 31, 265, 10.1016/j.bpg.2017.05.003

Rehermann, 1996, Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients, J Virol, 70, 7092, 10.1128/JVI.70.10.7092-7102.1996

Knolle, 2014, Hepatic immune regulation and its involvement in viral hepatitis infection, Gastroenterology, 146, 1193, 10.1053/j.gastro.2013.12.036

Das, 2008, Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection, J Exp Med, 205, 2111, 10.1084/jem.20072076

Fisicaro, 2017, Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B, Nat Med, 23, 327, 10.1038/nm.4275

Urbani, 2005, Acute phase HBV-specific T cell responses associated with HBV persistence after HBV/HCV coinfection, Hepatology, 41, 826, 10.1002/hep.20614

Das, 2012, IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection, J Immunol, 189, 3925, 10.4049/jimmunol.1103139

Xu, 2006, Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B, J Immunol, 177, 739, 10.4049/jimmunol.177.1.739

Pallett, 2015, Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells, Nat Med, 21, 591, 10.1038/nm.3856

Peppa, 2013, Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion, J Exp Med, 210, 99, 10.1084/jem.20121172

Bertoletti, 2016, Adaptive immunity in HBV infection, J Hepatol, 64, S71, 10.1016/j.jhep.2016.01.026

Vanwolleghem, 2015, Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells, Hepatology, 62, 87, 10.1002/hep.27805

Paul, 2017, Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: a meta-analysis, Hepatology, 66, 379, 10.1002/hep.29082

Perrillo, 2015, American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy, Gastroenterology, 148, 221, 10.1053/j.gastro.2014.10.038

Mason, 2016, HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant, Gastroenterology, 151, 986, 10.1053/j.gastro.2016.07.012

Tjwa, 2016, Similar frequencies, phenotype and activation status of intrahepatic NK cells in chronic HBV patients after long-term treatment with tenofovir disoproxil fumarate (TDF), Antiviral Res, 132, 70, 10.1016/j.antiviral.2016.05.016

Liu, 2014, Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection, PLoS Pathog, 10, e1003856, 10.1371/journal.ppat.1003856

Bohne, 2008, T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes, Gastroenterology, 134, 239, 10.1053/j.gastro.2007.11.002

Gehring, 2011, Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines, J Hepatol, 55, 103, 10.1016/j.jhep.2010.10.025

Koh, 2013, A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus, Mol Ther Nucleic Acids, 2, e114, 10.1038/mtna.2013.43

Krebs, 2013, T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice, Gastroenterology, 145, 456, 10.1053/j.gastro.2013.04.047

Qasim, 2015, Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient, J Hepatol, 62, 486, 10.1016/j.jhep.2014.10.001

Tu, 2018, Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via NTCP-dependent uptake of enveloped virus particles, J Virol, 92, 10.1128/JVI.02007-17

Zhao, 2016, Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma, Nat Commun, 7, 12992, 10.1038/ncomms12992

Alter, 2018, A research agenda for curing chronic hepatitis B virus infection, Hepatology, 67, 1127, 10.1002/hep.29509

Block, 2018, Research priorities for the discovery of a cure for chronic hepatitis B: report of a workshop, Antiviral Res, 150, 93, 10.1016/j.antiviral.2017.12.006