{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:33:39Z","timestamp":1791254019664,"version":"4.1.0"},"reference-count":194,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010897","name":"Official Development Assistance","doi-asserted-by":"publisher","award":["Newton prize 2020"],"award-info":[{"award-number":["Newton prize 2020"]}],"id":[{"id":"10.13039\/100010897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","award":["SGL021\/1030"],"award-info":[{"award-number":["SGL021\/1030"]}],"id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Seedcorn funding Rosetrees\/Stoneygate Trust","award":["A2903"],"award-info":[{"award-number":["A2903"]}]},{"name":"Early Career Research Award from The Medical Research Foundation","award":["MRF-044-0004-F-GILL-C0823"],"award-info":[{"award-number":["MRF-044-0004-F-GILL-C0823"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C53575\/A29959"],"award-info":[{"award-number":["C53575\/A29959"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HUNTER funded through a partnership between Cancer Research UK, Fondazione AIRC and Fundacion Cientifica de la Asociacion Espanola Contra el Cancer.","award":["HUNTERS"],"award-info":[{"award-number":["HUNTERS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.<\/jats:p>","DOI":"10.3390\/cancers14051255","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T20:09:57Z","timestamp":1646078997000},"page":"1255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3097-5776","authenticated-orcid":false,"given":"Marco Y. W.","family":"Zaki","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt"},{"name":"National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-1413","authenticated-orcid":false,"given":"Ahmed M.","family":"Fathi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samara","family":"Samir","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nardeen","family":"Eldafashi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerolis Y.","family":"William","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiiada Hassan","family":"Nazmy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0734-5007","authenticated-orcid":false,"given":"Moustafa","family":"Fathy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upkar S.","family":"Gill","sequence":"additional","affiliation":[{"name":"Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4729-2173","authenticated-orcid":false,"given":"Shishir","family":"Shetty","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"Forner","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nrc3449","article-title":"Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma","volume":"13","author":"Arzumanyan","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","first-page":"1234","article-title":"Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD","volume":"61","author":"Reeves","year":"2016","journal-title":"Am. J. Dig. Dis."},{"key":"ref_5","first-page":"263","article-title":"Cancer in Low- and Middle-Income Countries: An Economic Overview","volume":"Volume 3","author":"Gelband","year":"2015","journal-title":"Disease Control Priorities"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1136\/bmj.326.7397.994","article-title":"Liver cancer in low and middle income countries","volume":"326","author":"Hall","year":"2003","journal-title":"BMJ"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/S0140-6736(15)61412-X","article-title":"Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013","volume":"386","author":"Schweitzer","year":"2015","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/S0140-6736(16)30579-7","article-title":"The global burden of viral hepatitis from 1990 to 2013: Findings from the Global Burden of Disease Study 2013","volume":"388","author":"Stanaway","year":"2016","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"186","DOI":"10.4254\/wjh.v10.i2.186","article-title":"Hepatitis C virus: Morphogenesis, infection and therapy","volume":"10","author":"Morozov","year":"2018","journal-title":"World J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: From T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","unstructured":"World Health Organization (WHO) (2017). Global Hepatitis Report 2017."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/j.vaccine.2011.12.116","article-title":"Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity","volume":"30","author":"Ott","year":"2012","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1080\/21645515.2020.1852869","article-title":"Long-term immune protection against HBV: Associated factors and determinants","volume":"17","author":"Mastrodomenico","year":"2021","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.11604\/pamj.supp.2017.27.3.11546","article-title":"Is hepatitis B birth dose vaccine needed in Africa?","volume":"27","author":"Tamandjou","year":"2017","journal-title":"Pan Afr. Med. J."},{"key":"ref_15","first-page":"21s","article-title":"Hepatitis B virus as the etiologic agent in hepatocellular carcinoma-epidemiologic consideration","volume":"2","author":"Beasley","year":"1982","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/S0140-6736(17)32152-9","article-title":"Global, regional, and national age-sex specific mortality for 264 causes of death, 1980\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"390","author":"Moraga","year":"2017","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1016\/j.jhep.2014.07.027","article-title":"Global epidemiology and genotype distribution of the hepatitis C virus infection","volume":"61","author":"Gower","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S2468-1253(16)30181-9","article-title":"Global prevalence and genotype distribution of hepatitis C virus infection in 2015: A modelling study","volume":"2","author":"Blach","year":"2016","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.jhep.2005.03.021","article-title":"Changing pattern of hepatitis C virus spread in rural areas of Egypt","volume":"43","author":"Arafa","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1053\/j.gastro.2018.08.060","article-title":"Approaches, Progress, and Challenges to Hepatitis C Vaccine Development","volume":"156","author":"Bailey","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1053\/j.gastro.2017.06.012","article-title":"Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents","volume":"153","author":"Kanwal","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.1038\/sj.emboj.7601841","article-title":"Cryo-electron microscopy of hepatitis B virions reveals variability in envelope capsid interactions","volume":"26","author":"Seitz","year":"2007","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/hep.26125","article-title":"A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus A-determinant","volume":"57","author":"Sureau","year":"2012","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00049","DOI":"10.7554\/eLife.00049","article-title":"Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus","volume":"1","author":"Yan","year":"2012","journal-title":"eLife"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Schreiner, S., and Nassal, M. (2017). A role for the host DNA damage response in hepatitis B virus cccDNA formation\u2014And beyond?. Viruses, 9.","DOI":"10.3390\/v9050125"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1055\/s-0033-1345717","article-title":"The molecular virology of hepatitis B virus","volume":"33","author":"Glebe","year":"2013","journal-title":"Semin. Liver Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/hep.20032","article-title":"Structural biology of hepatitis C virus","volume":"39","author":"Dubuisson","year":"2004","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zeisel, M.B., Felmlee, D.J., and Baumert, T.F. (2013). Hepatitis C virus entry. Hepatitis C Virus: From Molecular Virology to Antiviral Therapy, Springer.","DOI":"10.1007\/978-3-642-27340-7_4"},{"key":"ref_29","first-page":"7040","article-title":"Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA-Containing Particles","volume":"76","author":"Deforges","year":"2002","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1128\/JVI.73.2.1165-1174.1999","article-title":"A Phylogenetically Conserved Stem-Loop Structure at the 5\u2032 Border of the Internal Ribosome Entry Site of Hepatitis C Virus Is Required for Cap-Independent Viral Translation","volume":"73","author":"Honda","year":"1999","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Niepmann, M. (2013). Hepatitis C virus RNA translation. Hepatitis C Virus: From Molecular Virology to Antiviral Therapy, Springer.","DOI":"10.1007\/978-3-642-27340-7_6"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Moradpour, D., and Penin, F. (2013). Hepatitis C virus proteins: From structure to function. Hepatitis C Virus: From Molecular Virology to Antiviral Therapy, Springer.","DOI":"10.1007\/978-3-642-27340-7_5"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lohmann, V. (2013). Hepatitis C virus RNA replication. Hepatitis C Virus: From Molecular Virology to Antiviral Therapy, Springer.","DOI":"10.1007\/978-3-642-27340-7_7"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lindenbach, B.D. (2013). Virion assembly and release. Hepatitis C Virus: From Molecular Virology to Antiviral Therapy, Springer.","DOI":"10.1007\/978-3-642-27340-7_8"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"047","DOI":"10.1055\/s-2003-37590","article-title":"Natural History and Prognosis of Hepatitis B","volume":"23","author":"Fattovich","year":"2003","journal-title":"Semin. Liver Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nri1573","article-title":"Immunology of hepatitis B virus and hepatitis C virus infection","volume":"5","author":"Rehermann","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14913","DOI":"10.1073\/pnas.0406282101","article-title":"A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen","volume":"101","author":"Chen","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1053\/j.gastro.2004.07.004","article-title":"Evolution of hepatitis B virus during primary infection in humans: Transient generation of cytotoxic T-cell mutants","volume":"127","author":"Whalley","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/hep.23226","article-title":"Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection","volume":"50","author":"Quasdorff","year":"2009","journal-title":"Hepatology"},{"key":"ref_40","first-page":"897","article-title":"Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B","volume":"66","author":"Testoni","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1084\/jem.191.7.1247","article-title":"Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice","volume":"191","author":"Guidotti","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/nri2858","article-title":"Antigen-presenting cell function in the tolerogenic liver environment","volume":"10","author":"Thomson","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1053\/j.gastro.2015.09.026","article-title":"Interferon-\u03b3 and tumor necrosis factor-\u03b1 produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis","volume":"150","author":"Xia","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.antiviral.2016.03.008","article-title":"Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus","volume":"130","author":"Isorce","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e0142599","DOI":"10.1371\/journal.pone.0142599","article-title":"IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome","volume":"10","author":"Palumbo","year":"2015","journal-title":"PLoS ONE"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1172\/JCI58847","article-title":"IFN-\u03b1 inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome","volume":"122","author":"Belloni","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S2468-1253(18)30007-4","article-title":"Defective T-cell immunity in hepatitis B virus infection: Why therapeutic vaccination needs a helping hand","volume":"3","author":"Maini","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1128\/JVI.77.1.68-76.2003","article-title":"CD8 + T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection","volume":"77","author":"Thimme","year":"2003","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9652","DOI":"10.1128\/JVI.00867-09","article-title":"The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection","volume":"83","author":"Asabe","year":"2009","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1053\/j.gastro.2009.06.054","article-title":"Temporal Analysis of Early Immune Responses in Patients With Acute Hepatitis B Virus Infection","volume":"137","author":"Dunn","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nri.2016.69","article-title":"Immune responses and immunopathology in acute and chronic viral hepatitis","volume":"16","author":"Shin","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Shi, B., Ren, G., Hu, Y., Wang, S., Zhang, Z., and Yuan, Z. (2012). HBsAg Inhibits IFN-\u03b1 Production in Plasmacytoid Dendritic Cells through TNF-\u03b1 and IL-10 Induction in Monocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044900"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/hep.22751","article-title":"Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells","volume":"49","author":"Wu","year":"2008","journal-title":"Hepatology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1099\/vir.0.82959-0","article-title":"Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1","volume":"88","author":"Wu","year":"2007","journal-title":"J. Gen. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/hep.21482","article-title":"Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein","volume":"45","author":"Visvanathan","year":"2006","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1084\/jem.20061287","article-title":"Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell\u2013mediated liver damage","volume":"204","author":"Dunn","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1084\/jem.20121172","article-title":"Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell\u2013mediated deletion","volume":"210","author":"Peppa","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.ajg.2020.05.002","article-title":"TRAIL inhibits HBV replication and expression by down-regulating liver-enriched transcription factors","volume":"21","author":"Li","year":"2020","journal-title":"Arab J. Gastroenterol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.4049\/jimmunol.1601313","article-title":"T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System","volume":"198","author":"Huang","year":"2016","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.immuni.2014.05.003","article-title":"Type I Interferons Protect T Cells against NK Cell Attack Mediated by the Activating Receptor NCR1","volume":"40","author":"Crouse","year":"2014","journal-title":"Immunity"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.immuni.2014.05.004","article-title":"Type I Interferon Protects Antiviral CD8+ T Cells from NK Cell Cytotoxicity","volume":"40","author":"Xu","year":"2014","journal-title":"Immunity"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Gill, U.S., Peppa, D., Micco, L., Singh, H.D., Carey, I., Foster, G.R., Maini, M.K., and Kennedy, P.T.F. (2016). Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005788"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1128\/MMBR.64.1.51-68.2000","article-title":"Hepatitis B virus biology","volume":"64","author":"Seeger","year":"2000","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1172\/JCI200421593","article-title":"The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity","volume":"114","author":"Bowen","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1128\/JVI.02844-06","article-title":"Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection","volume":"81","author":"Boni","year":"2007","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.jhep.2019.06.028","article-title":"Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study","volume":"71","author":"Gane","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.3389\/fimmu.2020.01037","article-title":"Anti\u2013PD-1\/PD-L1 Blockade Immunotherapy Employed in Treating Hepatitis B Virus Infection\u2013Related Advanced Hepatocellular Carcinoma: A Literature Review","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6634","DOI":"10.4049\/jimmunol.178.10.6634","article-title":"B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B","volume":"178","author":"Chen","year":"2007","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Schurich, A., Pallett, L.J., Lubowiecki, M., Singh, H.D., Gill, U.S., Kennedy, P.T., Nastouli, E., Tanwar, S., Rosenberg, W., and Maini, M.K. (2013). The Third Signal Cytokine IL-12 Rescues the Anti-Viral Function of Exhausted HBV-Specific CD8 T Cells. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003208"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6359","DOI":"10.1038\/srep06359","article-title":"Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection","volume":"4","author":"Chen","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_72","first-page":"423181","article-title":"Changes of Costimulatory Molecule CD28 on Circulating CD8+T Cells Correlate with Disease Pathogenesis of Chronic Hepatitis B","volume":"2014","author":"Li","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cellimm.2009.02.008","article-title":"Altered T cell costimulation during chronic hepatitis B infection","volume":"257","author":"Barboza","year":"2009","journal-title":"Cell. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1189\/jlb.4A0415-152R","article-title":"Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection","volume":"98","author":"Dai","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nm.4275","article-title":"Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B","volume":"23","author":"Fisicaro","year":"2017","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.celrep.2016.06.078","article-title":"Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host","volume":"16","author":"Schurich","year":"2016","journal-title":"Cell Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nm.3856","article-title":"Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells","volume":"21","author":"Pallett","year":"2015","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1084\/jem.20162115","article-title":"IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection","volume":"214","author":"Pallett","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1136\/gutjnl-2018-317071","article-title":"Fine needle aspirates comprehensively sample intrahepatic immunity","volume":"68","author":"Gill","year":"2018","journal-title":"Gut"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/1743-422X-10-239","article-title":"Medical Virology of Hepatitis B: How it began and where we are now","volume":"10","author":"Gerlich","year":"2013","journal-title":"Virol. J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.3389\/fimmu.2020.582292","article-title":"The Multiple Functions of B Cells in Chronic HBV Infection","volume":"11","author":"Cai","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.jhepr.2019.05.001","article-title":"The oncogenic role of hepatitis delta virus in hepatocellular carcinoma","volume":"1","author":"Villanueva","year":"2019","journal-title":"JHEP Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/hep.22654","article-title":"Hepatitis delta virus inhibits alpha interferon signaling","volume":"49","author":"Pugnale","year":"2009","journal-title":"Hepatology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1128\/jvi.65.3.1099-1104.1991","article-title":"Production of hepatitis delta virus and suppression of helper hepatitis B virus in a human hepatoma cell line","volume":"65","author":"Wu","year":"1991","journal-title":"J. Virol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1053\/j.gastro.2021.07.027","article-title":"Liver-Resident Bystander CD8+ T Cells Contribute to Liver Disease Pathogenesis in Chronic Hepatitis D Virus Infection","volume":"161","author":"Kefalakes","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1136\/gutjnl-2014-306767","article-title":"Effects of HDV infection and pegylated interferon \u03b1 treatment on the natural killer cell compartment in chronically infected individuals","volume":"64","author":"Lunemann","year":"2014","journal-title":"Gut"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1093\/infdis\/jit561","article-title":"Compromised Function of Natural Killer Cells in Acute and Chronic Viral Hepatitis","volume":"209","author":"Lunemann","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.194.10.1395","article-title":"Determinants of Viral Clearance and Persistence during Acute Hepatitis C Virus Infection","volume":"194","author":"Thimme","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1002\/hep.20239","article-title":"Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees","volume":"39","author":"Major","year":"2004","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1002\/hep.24580","article-title":"Hepatitis C virus induces interferon-\u03bb and interferon-stimulated genes in primary liver cultures","volume":"54","author":"Marukian","year":"2011","journal-title":"Hepatology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","article-title":"Pathogen recognition and innate immunity","volume":"124","author":"Akira","year":"2006","journal-title":"Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/ni1087","article-title":"The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses","volume":"5","author":"Yoneyama","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7431","DOI":"10.1073\/pnas.1002301107","article-title":"Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection","volume":"107","author":"Takahashi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.virol.2019.01.024","article-title":"Activation of protein kinase R by hepatitis C virus RNA-dependent RNA polymerase","volume":"529","author":"Suzuki","year":"2019","journal-title":"Virology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1172\/JCI67714","article-title":"Emerging concepts in immunity to hepatitis C virus infection","volume":"123","author":"Rosen","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.jhep.2014.04.020","article-title":"KIR2DL3+NKG2A\u2212 natural killer cells are associated with protection from productive hepatitis C virus infection in people who inject drugs","volume":"61","author":"Thoens","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1053\/j.gastro.2010.01.006","article-title":"Activation of Natural Killer Cells During Acute Infection With Hepatitis C Virus","volume":"138","author":"Amadei","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1002\/hep.26353","article-title":"Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection","volume":"58","author":"Werner","year":"2013","journal-title":"Hepatology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1084\/jem.20011145","article-title":"Binding of the Hepatitis C Virus Envelope Protein E2 to CD81 Inhibits Natural Killer Cell Functions","volume":"195","author":"Tseng","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"6072","DOI":"10.4049\/jimmunol.173.10.6072","article-title":"Negative Regulation of NK Cell Activities by Inhibitory Receptor CD94\/NKG2A Leads to Altered NK Cell-Induced Modulation of Dendritic Cell Functions in Chronic Hepatitis C Virus Infection","volume":"173","author":"Jinushi","year":"2004","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1053\/j.gastro.2011.05.006","article-title":"Delayed Induction, Not Impaired Recruitment, of Specific CD8+ T Cells Causes the Late Onset of Acute Hepatitis C","volume":"141","author":"Shin","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"15661","DOI":"10.1073\/pnas.202608299","article-title":"Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease","volume":"99","author":"Thimme","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1136\/gutjnl-2011-300620","article-title":"T cell responses in hepatitis C: The good, the bad and the unconventional","volume":"61","author":"Klenerman","year":"2011","journal-title":"Gut"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1084\/jem.20030239","article-title":"Memory CD8+ T Cells Are Required for Protection from Persistent Hepatitis C Virus Infection","volume":"197","author":"Shoukry","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1126\/science.1088774","article-title":"HCV Persistence and Immune Evasion in the Absence of Memory T Cell Help","volume":"302","author":"Grakoui","year":"2003","journal-title":"Science"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Kared, H., Fabre, T., B\u00e9dard, N., Bruneau, J., and Shoukry, N.H. (2013). Galectin-9 and IL-21 Mediate Cross-regulation between Th17 and Treg Cells during Acute Hepatitis C. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003422"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"10149","DOI":"10.1073\/pnas.0403519101","article-title":"Neutralizing antibody response during acute and chronic hepatitis C virus infection","volume":"101","author":"Logvinoff","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1073\/pnas.0607026104","article-title":"Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C","volume":"104","author":"Pestka","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1136\/gut.2005.076463","article-title":"Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C","volume":"55","author":"Nattermann","year":"2006","journal-title":"Gut"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.jhep.2010.03.018","article-title":"Altered interferon-\u03b1-signaling in natural killer cells from patients with chronic hepatitis C virus infection","volume":"53","author":"Miyagi","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1053\/j.gastro.2009.05.047","article-title":"Natural Killer Cell Functional Dichotomy in Chronic Hepatitis B and Chronic Hepatitis C Virus Infections","volume":"137","author":"Oliviero","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1053\/j.gastro.2009.08.066","article-title":"Natural Killer Cells Are Polarized Toward Cytotoxicity in Chronic Hepatitis C in an Interferon-Alfa\u2013Dependent Manner","volume":"138","author":"Ahlenstiel","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"12557","DOI":"10.1128\/JVI.00838-11","article-title":"Cell-to-Cell Contact with Hepatitis C Virus-Infected Cells Reduces Functional Capacity of Natural Killer Cells","volume":"85","author":"Yoon","year":"2011","journal-title":"J. Virol."},{"key":"ref_114","first-page":"1226","article-title":"Hepatitis C Virus Entry into Macrophages\/Monocytes Mainly Depends on the Phagocytosis of Macrophages","volume":"64","author":"Liu","year":"2018","journal-title":"Am. J. Dig. Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/hep.29170","article-title":"Hepatitis C virus-induced CCL5 secretion from macrophages activates hepatic stellate cells","volume":"66","author":"Sasaki","year":"2017","journal-title":"Hepatology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.jhep.2013.04.022","article-title":"IFN-\u03b3 production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells","volume":"59","author":"Zhang","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"S\u00e8ne, D., Levasseur, F., Abel, M., Lambert, M., Camous, X., Hernandez, C., P\u00e8ne, V., Rosenberg, A.R., Jouvin-Marche, E., and Marche, P. (2010). Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001184"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0168-8278(98)80385-1","article-title":"Recurrence of hepatitis C virus after loss of virus specific CD4+ T cell response in acute hepatitis C","volume":"28","author":"Gerlach","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_119","first-page":"243","article-title":"Adaptive Immune Responses in Hepatitis C Virus Infection","volume":"369","author":"Thimme","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"9249","DOI":"10.1128\/JVI.00409-07","article-title":"Upregulation of PD-1 Expression on Circulating and Intrahepatic Hepatitis C Virus-Specific CD8 + T Cells Associated with Reversible Immune Dysfunction","volume":"81","author":"Palmer","year":"2007","journal-title":"J. Virol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1172\/JCI39133","article-title":"Hepatitis C virus versus innate and adaptive immune responses: A tale of coevolution and coexistence","volume":"119","author":"Rehermann","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1053\/j.gastro.2008.02.033","article-title":"Functional Restoration of HCV-Specific CD8 T Cells by PD-1 Blockade Is Defined by PD-1 Expression and Compartmentalization","volume":"134","author":"Nakamoto","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1128\/JVI.02021-06","article-title":"Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression","volume":"81","author":"Radziewicz","year":"2007","journal-title":"J. Virol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1053\/j.gastro.2013.10.022","article-title":"Liver Environment and HCV Replication Affect Human T-Cell Phenotype and Expression of Inhibitory Receptors","volume":"146","author":"Kroy","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Bengsch, B., Seigel, B., Ruhl, M., Timm, J., Kuntz, M., Blum, H.E., Pircher, H., and Thimme, R. (2010). Coexpression of PD-1, 2B4, CD160 and KLRG1 on Exhausted HCV-Specific CD8+ T Cells Is Linked to Antigen Recognition and T Cell Differentiation. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000947"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"15001","DOI":"10.1073\/pnas.1312772110","article-title":"Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)","volume":"110","author":"Fuller","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/hep.20669","article-title":"Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection","volume":"41","author":"Semmo","year":"2005","journal-title":"Hepatology"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"7860","DOI":"10.1128\/JVI.79.12.7860-7867.2005","article-title":"T Cells with a CD4 + CD25 + Regulatory Phenotype Suppress In Vitro Proliferation of Virus-Specific CD8 + T Cells during Chronic Hepatitis C Virus Infection","volume":"79","author":"Boettler","year":"2005","journal-title":"J. Virol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1002\/hep.20454","article-title":"An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection","volume":"40","author":"Cabrera","year":"2004","journal-title":"Hepatology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"7852","DOI":"10.1128\/JVI.79.12.7852-7859.2005","article-title":"Regulatory T Cells Suppress In Vitro Proliferation of Virus-Specific CD8 + T Cells during Persistent Hepatitis C Virus Infection","volume":"79","author":"Rushbrook","year":"2005","journal-title":"J. Virol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1172\/JCI200420515","article-title":"Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection","volume":"113","author":"Accapezzato","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1128\/JVI.01592-10","article-title":"Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission","volume":"85","author":"Brimacombe","year":"2011","journal-title":"J. Virol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1053\/j.gastro.2006.12.008","article-title":"Hepatitis C Virus Continuously Escapes From Neutralizing Antibody and T-Cell Responses During Chronic Infection In Vivo","volume":"132","author":"Yoon","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"8072","DOI":"10.1128\/JVI.00459-07","article-title":"Hepatitis C Virus Envelope Glycoprotein E2 Glycans Modulate Entry, CD81 Binding, and Neutralization","volume":"81","author":"Falkowska","year":"2007","journal-title":"J. Virol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"8101","DOI":"10.1128\/JVI.00127-07","article-title":"The Neutralizing Activity of Anti-Hepatitis C Virus Antibodies Is Modulated by Specific Glycans on the E2 Envelope Protein","volume":"81","author":"Helle","year":"2007","journal-title":"J. Virol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The Hallmarks of Cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41590-018-0044-z","article-title":"The immunology of hepatocellular carcinoma","volume":"19","author":"Ringelhan","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.21037\/tcr.2016.05.13","article-title":"The genetic heterogeneity of hepatocellular carcinoma and the implications for personalised medicine","volume":"5","author":"Zaki","year":"2016","journal-title":"Transl. Cancer Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1053\/j.gastro.2015.12.033","article-title":"Variable Intra-Tumor Genomic Heterogeneity of Multiple Lesions in Patients with Hepatocellular Carcinoma","volume":"150","author":"Xue","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1055\/s-0031-1297924","article-title":"HCV and HCC: Clinical Update and a Review of HCC-Associated Viral Mutations in theCoreGene","volume":"31","author":"Ahmad","year":"2011","journal-title":"Semin. Liver Dis."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.jhep.2021.04.049","article-title":"Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis","volume":"75","author":"Pinyol","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1053\/j.gastro.2015.05.061","article-title":"Genetic Landscape and Biomarkers of Hepatocellular Carcinoma","volume":"149","author":"Villanueva","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1016\/j.jhep.2016.02.021","article-title":"Mechanisms of HBV-induced hepatocellular carcinoma","volume":"64","author":"Levrero","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/cmi.2016.26","article-title":"NK cell education via nonclassical MHC and non-MHC ligands","volume":"14","author":"He","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Peppa, D., Micco, L., Javaid, A., Kennedy, P.T.F., Schurich, A., Dunn, C., Pallant, C., Ellis, G., Khanna, P., and Dusheiko, G. (2010). Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001227"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/cmi.2015.113","article-title":"miR-146a negatively regulates NK cell functions via STAT1 signaling","volume":"14","author":"Xu","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_148","first-page":"310","article-title":"Inhibitory Receptors Beyond T Cell Exhaustion","volume":"6","author":"Marraco","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1002\/hep.30317","article-title":"Natural Killer Cell\u2013Derived Interferon-Gamma Promotes Hepatocellular Carcinoma Through the Epithelial Cell Adhesion Molecule\u2013Epithelial-to-Mesenchymal Transition Axis in Hepatitis B Virus Transgenic Mice","volume":"69","author":"Chen","year":"2019","journal-title":"Hepatology"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fimmu.2013.00057","article-title":"NK Cells: A Double-Edged Sword in Chronic Hepatitis B Virus Infection","volume":"4","author":"Maini","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/hep.23983","article-title":"Accelerated liver fibrosis in hepatitis B virus transgenic mice: Involvement of natural killer T cells","volume":"53","author":"Jin","year":"2010","journal-title":"Hepatology"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"7654","DOI":"10.4049\/jimmunol.1000927","article-title":"CD137-Mediated Pathogenesis from Chronic Hepatitis to Hepatocellular Carcinoma in Hepatitis B Virus-Transgenic Mice","volume":"185","author":"Wang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_154","first-page":"1","article-title":"Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion","volume":"9","author":"Sun","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1136\/gutjnl-2018-316510","article-title":"Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma","volume":"68","author":"Lim","year":"2018","journal-title":"Gut"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1136\/gutjnl-2017-314904","article-title":"High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B","volume":"67","author":"Kim","year":"2017","journal-title":"Gut"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1053\/j.gastro.2016.07.012","article-title":"HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant","volume":"151","author":"Mason","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1136\/gutjnl-2020-323300","article-title":"Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg-negative chronic hepatitis B","volume":"70","author":"Svicher","year":"2021","journal-title":"Gut"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1084\/jem.191.8.1269","article-title":"The Role of Virus-Specific Cd8+ Cells in Liver Damage and Viral Control during Persistent Hepatitis B Virus Infection","volume":"191","author":"Maini","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.3389\/fimmu.2019.02240","article-title":"Heterogeneity of HBV-Specific CD8+ T-Cell Failure: Implications for Immunotherapy","volume":"10","author":"Heim","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41467-018-08096-8","article-title":"Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice","volume":"10","author":"Zong","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/hep.26054","article-title":"Impairment of CD4+cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma","volume":"58","author":"Fu","year":"2012","journal-title":"Hepatology"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1053\/j.gastro.2019.07.028","article-title":"An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents","volume":"157","author":"Moeini","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1053\/j.gastro.2017.06.007","article-title":"Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features","volume":"153","author":"Sia","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ccr.2012.07.023","article-title":"TGF-\u03b2-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma","volume":"22","author":"Yang","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/sji.12524","article-title":"Immune Regulation by T Regulatory Cells in Hepatitis B Virus-Related Inflammation and Cancer","volume":"85","author":"Trehanpati","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1053\/j.gastro.2007.03.102","article-title":"Increased Regulatory T Cells Correlate With CD8 T-Cell Impairment and Poor Survival in Hepatocellular Carcinoma Patients","volume":"132","author":"Fu","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","article-title":"NASH limits anti-tumour surveillance in immunotherapy-treated HCC","volume":"592","author":"Pfister","year":"2021","journal-title":"Nature"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nri3447","article-title":"The good, the bad and the ugly\u2014TFH cells in human health and disease","volume":"13","author":"Tangye","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_170","first-page":"2926","article-title":"Follicular helper T cell exhaustion induced by PD-L1 expression in hepatocellular carcinoma results in impaired cytokine expression and B cell help, and is associated with advanced tumor stages","volume":"8","author":"Zhou","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Jia, Y., Zeng, Z., Li, Y., Li, Z., Jin, L., Zhang, Z., Wang, L., and Wang, F.-S. (2015). Impaired Function of CD4+ T Follicular Helper (Tfh) Cells Associated with Hepatocellular Carcinoma Progression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117458"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1099\/vir.0.007211-0","article-title":"Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells","volume":"90","author":"Liao","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1053\/j.gastro.2006.10.038","article-title":"Large Hepatitis Delta Antigen Modulates Transforming Growth Factor-\u03b2 Signaling Cascades: Implication of Hepatitis Delta Virus\u2013Induced Liver Fibrosis","volume":"132","author":"Choi","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/nm.3251","article-title":"Pathogenesis of chronic viral hepatitis: Differential roles of T cells and NK cells","volume":"19","author":"Rehermann","year":"2013","journal-title":"Nat. Med."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature02924","article-title":"NF-\u03baB functions as a tumour promoter in inflammation-associated cancer","volume":"431","author":"Pikarsky","year":"2004","journal-title":"Nature"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-96076-2","article-title":"Key features of the environment promoting liver cancer in the absence of cirrhosis","volume":"11","author":"Zaki","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1002\/ijc.24720","article-title":"Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: An analysis based on gender differences","volume":"125","author":"Nakagawa","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"10847","DOI":"10.1074\/jbc.M110.217653","article-title":"Extracellular Hepatitis C Virus Core Protein Activates STAT3 in Human Monocytes\/Macrophages\/Dendritic Cells via an IL-6 Autocrine Pathway","volume":"286","author":"Tacke","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa0804525","article-title":"Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma","volume":"359","author":"Hoshida","year":"2008","journal-title":"New Engl. J. Med."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"30711","DOI":"10.1074\/jbc.M209623200","article-title":"Hepatitis C Virus NS5A Protein Modulates c-Jun N-terminal Kinase through Interaction with Tumor Necrosis Factor Receptor-associated Factor 2","volume":"278","author":"Park","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1101\/gad.1989311","article-title":"The role of JNK in the development of hepatocellular carcinoma","volume":"25","author":"Das","year":"2011","journal-title":"Genes Dev."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.it.2012.10.004","article-title":"Type I interferon response and innate immune sensing of cancer","volume":"34","author":"Fuertes","year":"2012","journal-title":"Trends Immunol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.cyto.2013.03.024","article-title":"High tumor necrosis factor-\u03b1\/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C","volume":"62","author":"Aroucha","year":"2013","journal-title":"Cytokine"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.ccr.2009.08.021","article-title":"A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma","volume":"16","author":"Haybaeck","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1111\/liv.12927","article-title":"Liver-infiltrating CD 8+ lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma","volume":"36","author":"Ramzan","year":"2016","journal-title":"Liver Int."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1002\/hep.27188","article-title":"Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue","volume":"60","author":"Piconese","year":"2014","journal-title":"Hepatology"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/hep.31502","article-title":"Targeting Tumor-Associated Antigens in Hepatocellular Carcinoma for Immunotherapy: Past Pitfalls and Future Strategies","volume":"73","author":"Lu","year":"2020","journal-title":"Hepatology"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1002\/hep.26731","article-title":"Immunodominance and functional alterations of tumor-associated antigen-specific CD8 + T-cell responses in hepatocellular carcinoma","volume":"59","author":"Flecken","year":"2013","journal-title":"Hepatology"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining \u2018T cell exhaustion\u2019","volume":"19","author":"Blank","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_190","first-page":"8","article-title":"Hepatitis B Treatment: What We Know Now and What Remains to Be Researched","volume":"3","author":"Lok","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1056\/NEJMoa1512610","article-title":"Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection","volume":"373","author":"Feld","year":"2015","journal-title":"New Engl. J. Med."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jhep.2017.06.026","article-title":"Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies","volume":"67","author":"Bruix","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_193","doi-asserted-by":"crossref","unstructured":"Eldafashi, N., Darlay, R., Shukla, R., McCain, M., Watson, R., Liu, Y., McStraw, N., Fathy, M., Fawzy, M., and Zaki, M. (2021). A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?. Cancers, 13.","DOI":"10.3390\/cancers13061412"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.jhep.2017.01.020","article-title":"Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals","volume":"66","author":"Prenner","year":"2017","journal-title":"J. Hepatol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/5\/1255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:29:44Z","timestamp":1760135384000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/5\/1255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":194,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cancers14051255"],"URL":"https:\/\/doi.org\/10.3390\/cancers14051255","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]}}}