{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:01:35Z","timestamp":1785132095233,"version":"3.55.0"},"reference-count":134,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Occult hepatitis B infection (OBI) is characterized by the persistence of replication-competent hepatitis B virus (HBV) DNA in the absence of detectable hepatitis B surface antigen (HBsAg). Although typically clinically silent, OBI remains associated with transfusion-transmitted infection, viral reactivation during immunosuppression, and an increased risk of hepatocellular carcinoma (HCC). The mechanisms underlying this persistent low-replicative state remain incompletely understood. In this review, we summarize current evidence supporting the concept that OBI is maintained through dynamic interactions among viral genetic adaptation, host genetic and epigenetic regulation, and the intrahepatic immune microenvironment. Building upon these observations, we propose the immune-mediated microcosm as a conceptual framework describing how these processes may interact to sustain long-term immune equilibrium. We further discuss emerging evidence for coordinated viral and host genetic remodeling, immunometabolic regulation, and immune checkpoint signaling, while explicitly distinguishing mechanisms supported by direct evidence in OBI from those inferred from chronic hepatitis B, hepatocellular carcinoma, or experimental models. Finally, we examine the implications of this framework for biomarker discovery, risk stratification, and therapeutic development, while emphasizing the current evidential limitations and the need for direct validation in human OBI. Rather than providing a definitive mechanistic model, this framework is intended to facilitate mechanistic investigation, generate experimentally testable hypotheses, and help identify priorities for future research into OBI pathogenesis.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1899891","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:40:03Z","timestamp":1785130803000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The immunoecology of occult hepatitis B virus infection: genetic remodeling and the immune-mediated microcosm"],"prefix":"10.3389","volume":"17","author":[{"given":"Feng","family":"Wang","sequence":"first","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Wang","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiguo","family":"Xu","sequence":"additional","affiliation":[{"name":"Huzhou College of Life and Health","place":["Huzhou, China"]},{"name":"Union East China Stem Cell Genetic Engineering Co., Ltd.","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zequn","family":"Ou","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Yang","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxian","family":"Fei","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxian","family":"Song","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhu","family":"Chen","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Lv","sequence":"additional","affiliation":[{"name":"Huzhou Central Blood Station","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.jhep.2019.03.034","article-title":"Update of the statements on biology and clinical impact of occult hepatitis B virus infection","volume":"71","author":"Raimondo","year":"2019","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316490","article-title":"Multiple HBV transfusion transmissions from undetected occult infections: revising the minimal infectious dose","volume":"68","author":"Candotti","year":"2019","journal-title":"Gut"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13928","article-title":"Occult hepatitis B virus infection and current perspectives on global WHO 2030 eradication","volume":"31","author":"Saravanan","year":"2024","journal-title":"J Viral Hepat"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2019.08.001","article-title":"Improved detection of early acute, late acute, and occult hepatitis B infections by an increased sensitivity HBsAg assay","volume":"118","author":"Kuhns","year":"2019","journal-title":"J Clin Virol Off Publ Pan Am Soc Clin Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.06.016","article-title":"Poor efficacy of nucleic acid testing in identifying occult HBV infection and consequences for safety of blood supply in Italy","volume":"63","author":"Spreafico","year":"2015","journal-title":"J Hepatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(22)00201-1","article-title":"Prevalence of occult hepatitis B virus infection in adults: a systematic review and meta-analysis","volume":"7","author":"Im","year":"2022","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0131912","article-title":"Occult hepatitis B virus infection in Nigerian blood donors and hepatitis B virus transmission risks","volume":"10","author":"Oluyinka","year":"2015","journal-title":"PloS One"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.transci.2017.03.010","article-title":"Residual risk of HIV, HCV and HBV in Canada","volume":"56","author":"O\u2019Brien","year":"2017","journal-title":"Transfus Apher Sci Off J World Apher Assoc Off J Eur Soc Haemapheresis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.56.7081","article-title":"Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study","volume":"32","author":"Seto","year":"2014","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-04-848044","article-title":"Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy","volume":"133","author":"Kusumoto","year":"2019","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.3795","article-title":"Chronic hepatitis B infection: a review","volume":"319","author":"Tang","year":"2018","journal-title":"JAMA"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2019.06.029","article-title":"Among patients with undetectable hepatitis B surface antigen and hepatocellular carcinoma, a high proportion has integration of HBV DNA into hepatocyte DNA and no cirrhosis","volume":"18","author":"Wong","year":"2020","journal-title":"Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.05.042","article-title":"Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance","volume":"73","author":"Mak","year":"2020","journal-title":"J Hepatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-025-02805-2","article-title":"Exploratory analysis of HLA SNPs associated with occult HBV infection: a multicenter case-control study in Chinese blood donors","volume":"145","author":"Zhou","year":"2025","journal-title":"Hum Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.2102","article-title":"Haplotype-dependent HLA-DRB1-DQB1 susceptibility to occult HBV infection in Xi\u2019an Han population","volume":"11","author":"Wang","year":"2023","journal-title":"Mol Genet Genomic Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2020.104564","article-title":"The sK122R mutation of hepatitis B virus (HBV) is associated with occult HBV infection: analysis of a large cohort of Chinese patients","volume":"130","author":"Wang","year":"2020","journal-title":"J Clin Virol Off Publ Pan Am Soc Clin Virol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/trf.14046","article-title":"Characterization of hepatitis B virus (HBV) preS\/S gene mutations in blood donors with occult HBV infection in the Baoji area of North China","volume":"57","author":"Liao","year":"2017","journal-title":"Transfusion (Paris)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s12985-024-02366-2","article-title":"Effect of S-region mutations on HBsAg in HBsAg-negative HBV-infected patients","volume":"21","author":"Liu","year":"2024","journal-title":"Virol J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27604","article-title":"Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression","volume":"61","author":"Salpini","year":"2015","journal-title":"Hepatology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/s13027-018-0179-4","article-title":"Quasispecies variant of pre-S\/S gene in HBV-related hepatocellular carcinoma with HBs antigen positive and occult infection","volume":"13","author":"Hatazawa","year":"2018","journal-title":"Infect Agent Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s12879-018-3161-2","article-title":"Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe","volume":"18","author":"Colagrossi","year":"2018","journal-title":"BMC Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.12732","article-title":"Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment","volume":"24","author":"Lok","year":"2017","journal-title":"J Viral Hepat"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.11.004","article-title":"N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape","volume":"60","author":"Yu","year":"2014","journal-title":"J Hepatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/v12020251","article-title":"A hyper-glycosylation of HBV surface antigen correlates with HBsAg-negativity at immunosuppression-driven HBV reactivation in vivo and hinders HBsAg recognition in vitro","volume":"12","author":"Salpini","year":"2020","journal-title":"Viruses"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.012740-0","article-title":"Biological significance of amino acid substitutions in hepatitis B surface antigen (HBsAg) for glycosylation, secretion, antigenicity and immunogenicity of HBsAg and hepatitis B virus replication","volume":"91","author":"Wu","year":"2010","journal-title":"J Gen Virol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.49540","article-title":"Occult hepatitis B virus infection in maintenance hemodialysis patients: prevalence and mutations in \u201ca\u201d determinant","volume":"17","author":"Tang","year":"2020","journal-title":"Int J Med Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-022-00496-2","article-title":"High resolution HLA-DRB1 analysis and shared molecular amino acid signature of DR\u03b21 molecules in occult hepatitis B infection","volume":"23","author":"Wang","year":"2022","journal-title":"BMC Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/s12985-017-0865-7","article-title":"Genetic polymorphisms of HLA-DP and isolated anti-HBc are important subsets of occult hepatitis B infection in Indonesian blood donors: a case-control study","volume":"14","author":"Mardian","year":"2017","journal-title":"Virol J"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/srep24767","article-title":"Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis","volume":"6","author":"Nishida","year":"2016","journal-title":"Sci Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13405","article-title":"Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population","volume":"37","author":"Trinks","year":"2017","journal-title":"Liver Int Off J Int Assoc Study Liver"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086007","article-title":"Genetic association of human leukocyte antigens with chronicity or resolution of hepatitis B infection in Thai population","volume":"9","author":"Posuwan","year":"2014","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1086\/597614","article-title":"Methylation regulates hepatitis B viral protein expression","volume":"199","author":"Vivekanandan","year":"2009","journal-title":"J Infect Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110442","article-title":"Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection","volume":"9","author":"Zhang","year":"2014","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1159\/000321450","article-title":"Replicative activity of hepatitis B virus is negatively associated with methylation of covalently closed circular DNA in advanced hepatitis B virus infection","volume":"54","author":"Kim","year":"2011","journal-title":"Intervirology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1518090112","article-title":"Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation","volume":"112","author":"Tropberger","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1042\/CS20210392","article-title":"SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome","volume":"135","author":"Yu","year":"2021","journal-title":"Clin Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29912","article-title":"SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3-9 homolog 1 and SET domain containing 1A histone methyltransferases","volume":"68","author":"Ren","year":"2018","journal-title":"Hepatology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.09.019","article-title":"Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx","volume":"74","author":"Cheng","year":"2021","journal-title":"J Hepatol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.06.023","article-title":"HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase","volume":"63","author":"Rivi\u00e8re","year":"2015","journal-title":"J Hepatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nature17170","article-title":"Hepatitis B virus X protein identifies the Smc5\/6 complex as a host restriction factor","volume":"531","author":"Decorsi\u00e8re","year":"2016","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24551","article-title":"Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma","volume":"54","author":"Wong","year":"2011","journal-title":"Hepatology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jhep.2024.02.017","article-title":"Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity","volume":"81","author":"Narmada","year":"2024","journal-title":"J Hepatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.03.021","article-title":"Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: a new tool to detect occult infection","volume":"69","author":"Caviglia","year":"2018","journal-title":"J Hepatol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2021.0283","article-title":"Approaches to quantifying hepatitis B virus covalently closed circular DNA","volume":"28","author":"Zhang","year":"2022","journal-title":"Clin Mol Hepatol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-015-9666-5","article-title":"Will a second biopsy sample affect treatment decisions in patients with chronic hepatitis B","volume":"10","author":"Ekiz","year":"2016","journal-title":"Hepatol Int"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/BF02235164","article-title":"Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy","volume":"16","author":"Soloway","year":"1971","journal-title":"Am J Dig Dis"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2022.100449","article-title":"Targeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B","volume":"4","author":"van Buuren","year":"2022","journal-title":"JHEP Rep Innov Hepatol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314873","article-title":"Liver sampling: a vital window into HBV pathogenesis on the path to functional cure","volume":"67","author":"Gill","year":"2018","journal-title":"Gut"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100841","article-title":"Evaluation of the HBV liver reservoir with fine needle aspirates","volume":"5","author":"Testoni","year":"2023","journal-title":"JHEP Rep Innov Hepatol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1186\/s12967-025-07131-9","article-title":"A single-cell digital PCR method tailored for quantification of HBV DNA positive cells in liver biopsy tissues","volume":"23","author":"Li","year":"2025","journal-title":"J Transl Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.02071-24","article-title":"Identification and characteristics of mutations promoting occult HBV infection by ultrasensitive HBsAg assay","volume":"63","author":"Song","year":"2025","journal-title":"J Clin Microbiol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/s41392-024-01918-w","article-title":"Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases","volume":"9","author":"Yao","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"B54","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1186\/s13046-022-02531-x","article-title":"Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-\u03baBp65\/HK2 signalling","volume":"41","author":"Chen","year":"2022","journal-title":"J Exp Clin Cancer Res CR"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202507068","article-title":"Lactylated SPTAN1 accelerates hepatocellular carcinoma progression by promoting NOTCH1\/HES1 activation and immunosuppression","volume":"13","author":"Wang","year":"2026","journal-title":"Adv Sci"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.16739","article-title":"Bioinformatics and experimental validation were combined to explore lactylation-related biomarkers in HBV-associated acute liver failure","volume":"39","author":"Pei","year":"2024","journal-title":"J Gastroenterol Hepatol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.3393","article-title":"Human leukocyte antigen class I association with occult hepatitis B virus infection in the Shaanxi Han group: Analysis at the haplotype level","volume":"24","author":"Wang","year":"2022","journal-title":"J Gene Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1489770","article-title":"Differences in the intrahepatic expression of immune checkpoint molecules on T cells and natural killer cells in chronic HBV patients","volume":"15","author":"Dumolard","year":"2024","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"4078","DOI":"10.1016\/j.cell.2024.05.038","article-title":"Therapeutic potential of co-signaling receptor modulation in hepatitis B","volume":"187","author":"Andreata","year":"2024","journal-title":"Cell"},{"key":"B60","doi-asserted-by":"publisher","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":"B61","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1007\/s12072-020-10125-y","article-title":"Liver damage favors the eliminations of HBV integration and clonal hepatocytes in chronic hepatitis B","volume":"15","author":"Hu","year":"2021","journal-title":"Hepatol Int"},{"key":"B62","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.cell.2015.03.005","article-title":"Immunosurveillance of the liver by intravascular effector CD8(+) T cells","volume":"161","author":"Guidotti","year":"2015","journal-title":"Cell"},{"key":"B63","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1016\/j.immuni.2021.05.005","article-title":"Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming","volume":"54","author":"De Simone","year":"2021","journal-title":"Immunity"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-025-02199-3","article-title":"CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming","volume":"26","author":"Venzin","year":"2025","journal-title":"Nat Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200050","article-title":"Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes","volume":"217","author":"Pallett","year":"2020","journal-title":"J Exp Med"},{"key":"B66","doi-asserted-by":"publisher","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":"B67","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15226","article-title":"Myeloid-derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy","volume":"49","author":"Pal","year":"2019","journal-title":"Aliment Pharmacol Ther"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103139","article-title":"IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection","volume":"189","author":"Das","year":"2012","journal-title":"J Immunol"},{"key":"B69","doi-asserted-by":"publisher","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":"B70","doi-asserted-by":"publisher","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":"B71","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1409079","article-title":"Multi-omic molecular characterization and diagnostic biomarkers for occult hepatitis B infection and HBsAg-positive hepatitis B infection","volume":"15","author":"Jiang","year":"2024","journal-title":"Front Endocrinol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903670","article-title":"An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells","volume":"185","author":"Mezrich","year":"2010","journal-title":"J Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1474853","article-title":"Monocyte-derived Galectin-9 and PD-L1 differentially impair adaptive and innate immune response in chronic HBV infection and their expression remain unaltered after antiviral therapy","volume":"15","author":"Dey","year":"2024","journal-title":"Front Immunol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"683","DOI":"10.3350\/cmh.2025.0842","article-title":"Dissecting antibody-mediated natural killer cell effects reveals a cytotoxic CX3CR1+KLRC2-CD16hi subset linked to hepatitis B virus outcomes","volume":"32","author":"Tang","year":"2026","journal-title":"Clin Mol Hepatol"},{"key":"B75","doi-asserted-by":"publisher","first-page":"101996","DOI":"10.1016\/j.jcyt.2025.10.006","article-title":"Expanded adaptive NKG2C+ NK cells exhibit potent ADCC and functional responses against HBV-infected hepatoma cell lines","volume":"28","author":"Koki\u00e7i","year":"2026","journal-title":"Cytotherapy"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2025.106093","article-title":"CD163 impairs HBV clearance in mice by regulating intrahepatic T cell immune response via an IL-10-dependent mechanism","volume":"235","author":"Liu","year":"2025","journal-title":"Antiviral Res"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330541","article-title":"Enolase: a metabolic checkpoint behind diverse exhaustion stages of CD8+ T cells in chronic HBV and HCV","volume":"72","author":"Le Bert","year":"2023","journal-title":"Gut"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.scib.2025.03.038","article-title":"The core cellular network modulates immune phenotype switching in hepatitis B","volume":"70","author":"Chen","year":"2025","journal-title":"Sci Bull"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1172\/JCI121957","article-title":"PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection","volume":"128","author":"Salimzadeh","year":"2018","journal-title":"J Clin Invest"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.11.030","article-title":"Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients","volume":"70","author":"Testoni","year":"2019","journal-title":"J Hepatol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01275-19","article-title":"Diagnostic value of detection of pregenomic RNA in sera of hepatitis B virus-infected patients with different clinical outcomes","volume":"58","author":"Lin","year":"2020","journal-title":"J Clin Microbiol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae054","article-title":"New window into hepatitis B in Africa: Liver sampling combined with single-cell omics enables deep and longitudinal assessment of intrahepatic immunity in Zambia","volume":"230","author":"Musonda","year":"2024","journal-title":"J Infect Dis"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00145-11","article-title":"Characterization of occult hepatitis B virus infection from blood donors in China","volume":"49","author":"Zheng","year":"2011","journal-title":"J Clin Microbiol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1620-6","article-title":"Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming","volume":"574","author":"B\u00e9n\u00e9chet","year":"2019","journal-title":"Nature"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2012.1","article-title":"Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer","volume":"9","author":"Torres","year":"2012","journal-title":"Nat Rev Clin Oncol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26718","article-title":"Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study","volume":"59","author":"Hsu","year":"2014","journal-title":"Hepatology"},{"key":"B87","doi-asserted-by":"publisher","first-page":"30","DOI":"10.7326\/M15-1121","article-title":"Hepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta-analysis","volume":"164","author":"Paul","year":"2016","journal-title":"Ann Intern Med"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1002\/lt.23644","article-title":"Liver transplantation in hepatitis B core-negative recipients using livers from hepatitis B core-positive donors: a 13-year experience","volume":"19","author":"Bohorquez","year":"2013","journal-title":"Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000000777","article-title":"Rational basis for optimizing short and long-term hepatitis B virus prophylaxis post liver transplantation: role of hepatitis B immune globulin","volume":"99","author":"Roche","year":"2015","journal-title":"Transplantation"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e3182845f97","article-title":"Prevention of de novo hepatitis B in recipients of core antibody-positive livers with lamivudine and other nucleos(t)ides: a 12-year experience","volume":"95","author":"Chang","year":"2013","journal-title":"Transplantation"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.7326\/M17-0377","article-title":"Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration Adverse Event Reporting System","volume":"166","author":"Bersoff-Matcha","year":"2017","journal-title":"Ann Intern Med"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(18)30002-5","article-title":"Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis","volume":"3","author":"M\u00fccke","year":"2018","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2017.1325869","article-title":"Hepatitis B reactivation during or after direct acting antiviral therapy - implication for susceptible individuals","volume":"16","author":"Holmes","year":"2017","journal-title":"Expert Opin Drug Saf"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.12754","article-title":"HBV reactivation in patients with HCV\/HBV cirrhosis on treatment with direct-acting antivirals","volume":"25","author":"Calvaruso","year":"2018","journal-title":"J Viral Hepat"},{"key":"B95","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1186\/s40425-019-0808-5","article-title":"Hepatitis B virus reactivation in cancer patients with positive hepatitis B surface antigen undergoing PD-1 inhibition","volume":"7","author":"Zhang","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000358","article-title":"Hepatitis B virus reactivation in cancer patients treated with immune checkpoint inhibitors","volume":"44","author":"Burns","year":"2021","journal-title":"J Immunother"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001072","article-title":"Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma","volume":"8","author":"Lee","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B98","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1053\/j.gastro.2015.11.050","article-title":"Hepatitis B virus--specific and global T-cell dysfunction in chronic hepatitis B","volume":"150","author":"Park","year":"2016","journal-title":"Gastroenterology"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.08.013","article-title":"Molecular recalibration of PD-1+ antigen-specific T cells from blood and liver","volume":"26","author":"Otano","year":"2018","journal-title":"Mol Ther J Am Soc Gene Ther"},{"key":"B100","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1136\/gutjnl-2018-316644","article-title":"Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection","volume":"68","author":"Hoogeveen","year":"2019","journal-title":"Gut"},{"key":"B101","doi-asserted-by":"publisher","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":"B102","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25510","article-title":"High rate of occult hepatitis B virus infection in hemodialysis units of KwaZulu-Natal, South Africa","volume":"91","author":"Msomi","year":"2019","journal-title":"J Med Virol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12807","article-title":"Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma","volume":"35","author":"Saitta","year":"2015","journal-title":"Liver Int Off J Int Assoc Study Liver"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3547","article-title":"Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer","volume":"48","author":"Fujimoto","year":"2016","journal-title":"Nat Genet"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-323153","article-title":"Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma","volume":"71","author":"P\u00e9neau","year":"2022","journal-title":"Gut"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.12380","article-title":"Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection","volume":"22","author":"Tu","year":"2015","journal-title":"J Viral Hepat"},{"key":"B107","doi-asserted-by":"publisher","first-page":"93","DOI":"10.3892\/ol.2022.13213","article-title":"Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma","volume":"23","author":"Tomiyama","year":"2022","journal-title":"Oncol Lett"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2022.105375","article-title":"A longitudinal study to detect hepatitis B surface and core-related antigens in chronic hepatitis B patients with hepatitis B surface antigen seroclearance using highly sensitive assays","volume":"160","author":"Wong","year":"2023","journal-title":"J Clin Virol Off Publ Pan Am Soc Clin Virol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29109","article-title":"Kinetics of HBcrAg and HBsAg using highly sensitive iTACT assays in chronic hepatitis B patients with HBsAg seroclearance","volume":"95","author":"Suzuki","year":"2023","journal-title":"J Med Virol"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2024.116636","article-title":"SATCAS: A CRISPR\/Cas13a-based simultaneous amplification and testing platform for one-pot RNA detection and SNPs distinguish in clinical diagnosis","volume":"263","author":"Wang","year":"2024","journal-title":"Biosens Bioelectron"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-321116","article-title":"Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation","volume":"70","author":"Seto","year":"2021","journal-title":"Gut"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2025.108139","article-title":"The diagnostic value of hepatitis B core-related antigen in occult hepatitis B virus infection and its related hepatocellular carcinoma","volume":"161","author":"Zhan","year":"2025","journal-title":"Int J Infect Dis IJID Off Publ Int Soc Infect Dis"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad140","article-title":"Occult hepatitis B virus infection and liver fibrosis in Chinese patients","volume":"228","author":"Tang","year":"2023","journal-title":"J Infect Dis"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaf554","article-title":"Noninvasive detection of occult yet significant liver pathology in alanine aminotransferase-normal chronic hepatitis B: A multicenter study","volume":"233","author":"Li","year":"2026","journal-title":"J Infect Dis"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1111\/liv.16064","article-title":"What is the benefit of prophylaxis to prevent HBV reactivation in HBsAg-negative anti-HBc-positive patients? Meta-analysis and decision curve analysis","volume":"44","author":"Celsa","year":"2024","journal-title":"Liver Int Off J Int Assoc Study Liver"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2026.115650","article-title":"HBV biomarkers outperform host genetic variants in distinguishing occult HBV infection from chronic carriers","volume":"29","author":"Zhou","year":"2026","journal-title":"iScience"},{"key":"B117","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1056\/NEJMoa2213429","article-title":"A phase 3, randomized trial of bulevirtide in chronic hepatitis D","volume":"389","author":"Wedemeyer","year":"2023","journal-title":"N Engl J Med"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.01.035","article-title":"Blocking viral entry with bulevirtide reduces the number of HDV-infected hepatocytes in human liver biopsies","volume":"80","author":"Allweiss","year":"2024","journal-title":"J Hepatol"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2210027","article-title":"Efficacy and safety of bepirovirsen in chronic hepatitis B infection","volume":"387","author":"Yuen","year":"2022","journal-title":"N Engl J Med"},{"key":"B120","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/hep.31008","article-title":"RNA interference therapy with ARC-520 results in prolonged hepatitis B surface antigen response in patients with chronic hepatitis B infection","volume":"72","author":"Yuen","year":"2020","journal-title":"Hepatology"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-333026","article-title":"Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989","volume":"74","author":"Mak","year":"2025","journal-title":"Gut"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2025.107689","article-title":"Inactivation of the key ORFs of HBV for antiviral therapy by non-cleavage base editing","volume":"205","author":"Qin","year":"2025","journal-title":"Microb Pathog"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2025.106326","article-title":"Suppression of HBV replication and expression by CRISPR\/Cas9 ribonucleoproteins","volume":"245","author":"Hill","year":"2026","journal-title":"Antiviral Res"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.10.027","article-title":"Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B","volume":"68","author":"Janssen","year":"2018","journal-title":"J Hepatol"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2021.100361","article-title":"Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib\/IIa study","volume":"3","author":"Ma","year":"2021","journal-title":"JHEP Rep Innov Hepatol"},{"key":"B126","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.jcyt.2018.02.002","article-title":"HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice","volume":"20","author":"Kruse","year":"2018","journal-title":"Cytotherapy"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-25-1245","article-title":"HBV-specific TCR-T cell therapy combining mRNA electroporation and lentiviral transduction: Treatment regimen for recurrent HBV-related HCC after liver transplantation","volume":"31","author":"Zhao","year":"2025","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2026.1768365","article-title":"Virus-directed CAR immunotherapies for chronic HBV and HIV: A systematic synthesis of preclinical and early clinical evidences","volume":"13","author":"Sleman","year":"2026","journal-title":"Front Med"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004473","article-title":"Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy","volume":"10","author":"Elliott","year":"2014","journal-title":"PloS Pathog"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0326-x","article-title":"Identification of preexisting adaptive immunity to Cas9 proteins in humans","volume":"25","author":"Charlesworth","year":"2019","journal-title":"Nat Med"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba9188","article-title":"MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates","volume":"12","author":"Hordeaux","year":"2020","journal-title":"Sci Transl Med"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.7230","article-title":"A polygenetic risk score combined with environmental factors better predict susceptibility to hepatocellular carcinoma in Chinese population","volume":"13","author":"Zou","year":"2024","journal-title":"Cancer Med"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.2072","article-title":"Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large B-cell lymphoma","volume":"3","author":"Lyman","year":"2020","journal-title":"JAMA Netw Open"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-025-12252-z","article-title":"Residual transfusion risk of occult hepatitis B transmission associated to genotypes A and E among blood donors in Yaound\u00e9, Cameroon","volume":"26","author":"Chouwat","year":"2025","journal-title":"BMC Infect Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1899891\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:40:04Z","timestamp":1785130804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1899891\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":134,"alternative-id":["10.3389\/fimmu.2026.1899891"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1899891","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"1899891"}}