Assessing immunological and virological responses in the liver: Implications for the cure of chronic hepatitis B virus infection

Revill, 2019, A global scientific strategy to cure hepatitis B, Lancet Gastroenterol Hepatol, 4, 545, 10.1016/S2468-1253(19)30119-0 Rehermann, 2019, Insights from antiviral therapy into immune responses to hepatitis B and C virus infection, Gastroenterology, 156, 369, 10.1053/j.gastro.2018.08.061 Le Bert, 2020, Effects of hepatitis B surface antigen on virus-specific and global T cells in patients with chronic hepatitis B virus infection, Gastroenterology, 159, 652, 10.1053/j.gastro.2020.04.019 Fanning, 2019, Therapeutic strategies for hepatitis B virus infection: towards a cure, Nat Rev Drug Discov, 18, 827, 10.1038/s41573-019-0037-0 Berzigotti, 2021, EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update, J Hepatol, 75, 659, 10.1016/j.jhep.2021.05.025 Parikh, 2017, Fibrosis assessment in patients with chronic hepatitis B virus (HBV) infection, Ann Translational Med, 5, 4, 10.21037/atm.2017.01.28 Mannan, 2014, A comparative evaluation of scoring systems for assessing necro-inflammatory activity and fibrosis in liver biopsies of patients with chronic viral hepatitis, J Clin Diagn Res: JCDR, 8, Fc08 Testoni, 2019, Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients, J Hepatol, 70, 615, 10.1016/j.jhep.2018.11.030 Giersch, 2017, Serum HBV pgRNA as a clinical marker for cccDNA activity, J Hepatol, 66, 460, 10.1016/j.jhep.2016.09.028 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 Tu, 2017, HBV DNA integration: molecular mechanisms and clinical implications, Viruses, 9, 10.3390/v9040075 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 Wong, 2016, A high-dimensional atlas of human T cell diversity reveals tissue-specific trafficking and cytokine signatures, Immunity, 45, 442, 10.1016/j.immuni.2016.07.007 Sprengers, 2005, Flow cytometry of fine-needle-aspiration biopsies: a new method to monitor the intrahepatic immunological environment in chronic viral hepatitis, J viral Hepat, 12, 507, 10.1111/j.1365-2893.2005.00626.x Gill, 2019, Fine needle aspirates comprehensively sample intrahepatic immunity, Gut, 68, 1493, 10.1136/gutjnl-2018-317071 Pembroke, 2014, The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon α treatment, Gut, 63, 515, 10.1136/gutjnl-2013-304472 Schurich, 2016, Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host, Cell Rep, 16, 1243, 10.1016/j.celrep.2016.06.078 Khakpoor, 2019, Spatiotemporal differences in presentation of CD8 T cell epitopes during hepatitis B virus infection, J Virol, 93, 10.1128/JVI.01457-18 Rydell, 2021, Quantification of viral RNA in multiple pieces of explant liver tissue shows distinct focal differences of hepatitis B infection, J Infect Dis Huang, 2021, Rapid turnover of hepatitis B virus covalently closed circular DNA indicated by monitoring emergence and reversion of signature-mutation in treated chronic hepatitis B patients, Hepatology, 73, 41, 10.1002/hep.31240 Balagopal, 2020, Single hepatocytes show persistence and transcriptional inactivity of hepatitis B, JCI Insight, 5, 10.1172/jci.insight.140584 Balagopal, 2020, Single hepatocyte hepatitis B virus transcriptional landscape in HIV coinfection, J Infect Dis, 221, 1462, 10.1093/infdis/jiz607 Volz, 2013, The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus, J Hepatol, 58, 861, 10.1016/j.jhep.2012.12.008 Mason, 2021, Hepatitis B virus DNA integration and clonal expansion of hepatocytes in the chronically infected liver, Viruses, 13, 210, 10.3390/v13020210 Pollicino, 2021, HBV-integration studies in the clinic: role in the natural history of infection, Viruses, 13, 10.3390/v13030368 Meier, 2021, Ubiquitous expression of HBsAg from integrated HBV DNA in patients with low viral load, J Hepatol, 75, 840, 10.1016/j.jhep.2021.04.051 Podlaha, 2019, Genomic modeling of hepatitis B virus integration frequency in the human genome, PloS one, 14, 10.1371/journal.pone.0220376 Suslov, 2021, Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity, J Hepatol, 74, 794, 10.1016/j.jhep.2020.11.003 Wooddell, 2017, RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg, Sci translational Med, 9, 10.1126/scitranslmed.aan0241 Yuen, 2021, Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment, Gut Yang, 2020, Permanent inactivation of HBV genomes by CRISPR/Cas9-Mediated non-cleavage base editing, Mol Ther Nucleic Acids, 20, 480, 10.1016/j.omtn.2020.03.005 Chow, 2020, Long term nucleos(t)ide analogue therapy reduced the extent of HBV DNA integration in chronic Hepatitis B patients, Hepatology, 71 Hsu, 2022, Inhibition of viral replication reduces transcriptionally active distinct hepatitis B virus integrations with implications on host gene dysregulation, Gastroenterology, 162, 1160, 10.1053/j.gastro.2021.12.286 Tu, 2018, Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via sodium taurocholate cotransporting polypeptide-dependent uptake of enveloped virus particles, J Virol, 92, 10.1128/JVI.02007-17 Choi, 2019, High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation, Aliment Pharmacol Ther, 50, 215, 10.1111/apt.15311 Kim, 2018, High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B, Gut, 67, 945, 10.1136/gutjnl-2017-314904 Tu, 2021, Hepatitis B virus DNA integration: in vitro models for investigating viral pathogenesis and persistence, Viruses, 13, 180, 10.3390/v13020180 Kennedy, 2017, Immune tolerant chronic hepatitis B: the unrecognized risks, Viruses, 9, 10.3390/v9050096 Bertoletti, 2012, Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection, Gut, 61, 1754, 10.1136/gutjnl-2011-301073 Svicher, 2021, Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg-negative chronic hepatitis B, Gut, 70, 2337, 10.1136/gutjnl-2020-323300 Péneau, 2022, Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma, Gut, 71, 616, 10.1136/gutjnl-2020-323153 Dandri, 2020, Epigenetic modulation in chronic hepatitis B virus infection, Semin Immunopathol, 42, 173, 10.1007/s00281-020-00780-6 Allweiss, 2020, In-vitro and in-vivo models for hepatitis B cure research, Curr Opin HIV AIDS, 15, 173, 10.1097/COH.0000000000000616 Hadziyannis, 2018, Viral biomarkers in chronic HBeAg negative HBV infection, Genes, 9, 469, 10.3390/genes9100469 Flecken, 2019, Mapping the heterogeneity of histone modifications on hepatitis B virus DNA using liver needle biopsies obtained from chronically infected patients, J Virol, 93, 10.1128/JVI.02036-18 Lebossé, 2020, Quantification and epigenetic evaluation of the residual pool of hepatitis B covalently closed circular DNA in long-term nucleoside analogue-treated patients, Scientific Rep, 10, 21097, 10.1038/s41598-020-78001-1 Volz, 2007, Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients, Gastroenterology, 133, 843, 10.1053/j.gastro.2007.06.057 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 Loomba, 2017, Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions, Gastroenterology, 152, 1297, 10.1053/j.gastro.2017.02.009 Maini, 2019, Restoring, releasing or replacing adaptive immunity in chronic hepatitis B, Nat Rev Gastroenterol Hepatol, 16, 662, 10.1038/s41575-019-0196-9 Hensel, 2021, Memory-like HCV-specific CD8(+) T cells retain a molecular scar after cure of chronic HCV infection, Nat Immunol, 22, 229, 10.1038/s41590-020-00817-w Schmidt, 2021, Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint, Nat Commun, 12, 2814, 10.1038/s41467-021-22967-7 Yates, 2021, Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans, Nat Immunol, 22, 1020, 10.1038/s41590-021-00979-1 Lucifora, 2014, Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA, Science (New York, NY), 343, 1221, 10.1126/science.1243462