{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:19:08Z","timestamp":1790360348545,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T00:00:00Z","timestamp":1628985600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia\u2010inducible factor 1 alpha (HIF1\u03b1) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis\u2010related scaring, leading <jats:italic toggle=\"yes\">inter alia<\/jats:italic> to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1\u03b1 stabilization.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We addressed whether HIF1\u03b1 interferes with immune\u2010mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and <jats:italic toggle=\"yes\">in situ<\/jats:italic> hybridization. The effect of HIF1\u03b1 induction\/stabilization on differentiated HepaRG or mice \u00b1 HBV \u00b1 LT\u03b2R\u2010agonist (BS1) was assessed <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. Induction of A3B and subsequent effects were analyzed by RT\u2010qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1\u03b1 levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune\u2010active patients. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, HIF1\u03b1 stabilization strongly impaired A3B expression and anti\u2010HBV effect. Interestingly, HIF1\u03b1 knockdown was sufficient to rescue the inhibition of A3B up\u2010regulation and \u2010mediated antiviral effects, whereas HIF2\u03b1 knockdown had no effect. HIF1\u03b1 stabilization decreased the level of v\u2010rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. Noteworthy, this function of HIF1\u03b1 was independent of its partner, aryl hydrocarbon receptor nuclear translocator.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, inhibiting HIF1\u03b1 expression or stabilization represents an anti\u2010HBV strategy in the context of immune\u2010mediated A3B induction. High HIF1\u03b1, mediated by hypoxia or inflammation, offers a reservoir for HBV survival <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and should be considered as a restricting factor in the development of immune therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31902","type":"journal-article","created":{"date-parts":[[2021,5,15]],"date-time":"2021-05-15T05:11:55Z","timestamp":1621055515000},"page":"1766-1781","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":34,"title":["Hypoxia\u2010Inducible Factor 1 Alpha\u2013Mediated RelB\/APOBEC3B Down\u2010regulation Allows Hepatitis B Virus Persistence"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-4442","authenticated-orcid":false,"given":"Tobias","family":"Riedl","sequence":"first","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"},{"name":"Faculty of Biosciences,Heidelberg University,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7898-6795","authenticated-orcid":false,"given":"Suzanne","family":"Faure\u2010Dupuy","sequence":"additional","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"},{"name":"Department of Infectious Diseases,Molecular Virology,Heidelberg University,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8858-8915","authenticated-orcid":false,"given":"Maude","family":"Rolland","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology and Signal Transduction,GIGA\u2010Institute,University of Li\u00e8ge,Li\u00e8ge,Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Schuehle","sequence":"additional","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"},{"name":"Faculty of Biosciences,Heidelberg University,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohier","family":"Hizir","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology and Signal Transduction,GIGA\u2010Institute,University of Li\u00e8ge,Li\u00e8ge,Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Calderazzo","sequence":"additional","affiliation":[{"name":"Division of Biostatistics,German Cancer Research Center (DKFZ),Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine,University of Oxford,Oxford,United Kingdom"},{"name":"Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI),University of Oxford,Oxford,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Wettengel","sequence":"additional","affiliation":[{"name":"Institute of Virology,Helmholtz Zentrum M\u00fcnchen,Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin Alexander","family":"Lopez","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology and Signal Transduction,GIGA\u2010Institute,University of Li\u00e8ge,Li\u00e8ge,Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Barnault","sequence":"additional","affiliation":[{"name":"Departement of Anesthesiology and Intensive Care Medicine,Molecular Intensive Care Medicine,University Hospital T\u00fcbingen,Eberhard\u2010Karls\u2010University,Tuebingen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valbona","family":"Mirakaj","sequence":"additional","affiliation":[{"name":"Departement of Anesthesiology and Intensive Care Medicine,Molecular Intensive Care Medicine,University Hospital T\u00fcbingen,Eberhard\u2010Karls\u2010University,Tuebingen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Prokosch","sequence":"additional","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danijela","family":"Heide","sequence":"additional","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Leuchtenberger","sequence":"additional","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schneider","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Based Protein Analysis Unit,German Cancer Research Center (DKFZ),Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"He\u00dfling","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Based Protein Analysis Unit,German Cancer Research Center (DKFZ),Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Stottmeier","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"},{"name":"German Center for Infection Research (DZIF),partner site Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5618-2817","authenticated-orcid":false,"given":"Isabel M.","family":"Wessbecher","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"},{"name":"Tissue Bank of the German Center for Infection Research (DZIF),Institute of Pathology,Heidelberg University Hospital,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Schirmacher","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"},{"name":"Tissue Bank of the German Center for Infection Research (DZIF),Institute of Pathology,Heidelberg University Hospital,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A","family":"McKeating","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine,University of Oxford,Oxford,United Kingdom"},{"name":"Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI),University of Oxford,Oxford,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-1911","authenticated-orcid":false,"given":"Ulrike","family":"Protzer","sequence":"additional","affiliation":[{"name":"Institute of Virology,Helmholtz Zentrum M\u00fcnchen,Munich,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9226-3419","authenticated-orcid":false,"given":"David","family":"Durantel","sequence":"additional","affiliation":[{"name":"INSERM,U1052,Cancer Research Center of Lyon (CRCL),University of Lyon (UCBL1),CNRS UMR_5286, Centre L\u00e9on B\u00e9rard (CLB),Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0482-7809","authenticated-orcid":false,"given":"Julie","family":"Lucifora","sequence":"additional","affiliation":[{"name":"INSERM,U1052,Cancer Research Center of Lyon (CRCL),University of Lyon (UCBL1),CNRS UMR_5286, Centre L\u00e9on B\u00e9rard (CLB),Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-1242","authenticated-orcid":false,"given":"Emmanuel","family":"Dejardin","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology and Signal Transduction,GIGA\u2010Institute,University of Li\u00e8ge,Li\u00e8ge,Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3135-2274","authenticated-orcid":false,"given":"Mathias","family":"Heikenwalder","sequence":"additional","affiliation":[{"name":"Division of Chronic Inflammation and Cancer,German Cancer Research Center (DKFZ),Heidelberg,Germany"},{"name":"Department of Infectious Diseases,Molecular Virology,Heidelberg University,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8,15]]},"reference":[{"key":"hep31902-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/s41573-019-0037-0","article-title":"Therapeutic strategies for hepatitis B virus infection: towards a cure","volume":"18","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"hep31902-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"5390","DOI":"10.1038\/s41598-018-23525-w","article-title":"Direct antiviral properties of TLR ligands against HBV replication in immune\u2010competent hepatocytes","volume":"8","year":"2018","journal-title":"Sci Rep"},{"key":"hep31902-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1080\/17460441.2018.1473372","article-title":"Recent advances in the discovery and development of TLR ligands as novel therapeutics for chronic HBV and HIV infections","volume":"13","year":"2018","journal-title":"Expert Opin Drug Discov"},{"key":"hep31902-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.jhep.2017.12.007","article-title":"Toll\u2010like receptor 7 agonist GS\u20109620 induces prolonged inhibition of HBV via a type I interferon\u2010dependent mechanism","volume":"68","year":"2018","journal-title":"J Hepatol"},{"key":"hep31902-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1126\/science.1243462","article-title":"Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA","volume":"343","year":"2014","journal-title":"Science"},{"key":"hep31902-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1053\/j.gastro.2018.03.027","article-title":"Nonlytic lymphocytes engineered to express virus\u2010specific T\u2010cell receptors limit HBV infection by activating APOBEC3","volume":"155","year":"2018","journal-title":"Gastroenterology"},{"key":"hep31902-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/JLB.2MR0717-310R","article-title":"Understanding the regulation of APOBEC3 expression: current evidence and much to learn","volume":"103","year":"2018","journal-title":"J Leukoc Biol"},{"key":"hep31902-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1136\/gutjnl-2018-317601","article-title":"APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression","volume":"68","year":"2019","journal-title":"Gut"},{"key":"hep31902-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.bcp.2006.08.007","article-title":"The alternative NF\u2010kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development","volume":"72","year":"2006","journal-title":"Biochem Pharmacol"},{"key":"hep31902-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S1074-7613(02)00423-5","article-title":"The lymphotoxin\u2010\u03b2 receptor induces different patterns of gene expression via two NF\u2010\u03baB pathways","volume":"17","year":"2002","journal-title":"Immunity"},{"key":"hep31902-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/wsbm.1331","article-title":"Signaling via the NF\u03baB system","volume":"8","year":"2016","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"hep31902-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/febs.13578","article-title":"NF\u2010\u03baB and HIF crosstalk in immune responses","volume":"283","year":"2016","journal-title":"FEBS J"},{"key":"hep31902-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1002\/ijc.29519","article-title":"HIF\u20101 at the crossroads of hypoxia, inflammation, and cancer","volume":"138","year":"2016","journal-title":"Int J Cancer"},{"key":"hep31902-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"15655","DOI":"10.1073\/pnas.232137699","article-title":"Infection of a human hepatoma cell line by hepatitis B virus","volume":"99","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31902-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.jhep.2011.02.015","article-title":"Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection","volume":"55","year":"2011","journal-title":"J Hepatol"},{"key":"hep31902-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.chom.2016.05.013","article-title":"A slow maturation process renders hepatitis B virus infectious","volume":"20","year":"2016","journal-title":"Cell Host Microbe"},{"key":"hep31902-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.jhep.2019.06.032","article-title":"Hepatitis B virus\u2010induced modulation of liver macrophage function promotes hepatocyte infection","volume":"71","year":"2019","journal-title":"J Hepatol"},{"key":"hep31902-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.antiviral.2016.03.008","article-title":"Antiviral activity of various interferons and pro\u2010inflammatory cytokines in non\u2010transformed cultured hepatocytes infected with hepatitis B virus","volume":"130","year":"2016","journal-title":"Antiviral Res"},{"key":"hep31902-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.ccr.2009.08.021","article-title":"A lymphotoxin\u2010driven pathway to hepatocellular carcinoma","volume":"16","year":"2009","journal-title":"Cancer Cell"},{"key":"hep31902-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nrc3621","article-title":"bHLH\u2010PAS proteins in cancer","volume":"13","year":"2013","journal-title":"Nat Rev Cancer"},{"key":"hep31902-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1189\/jlb.0513305","article-title":"RelB: an outlier in leukocyte biology","volume":"94","year":"2013","journal-title":"J Leukoc Biol"},{"key":"hep31902-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1126\/science.1162818","article-title":"The aryl hydrocarbon nuclear translocator alters CD30\u2010mediated NF\u2010kappaB\u2010dependent transcription","volume":"323","year":"2009","journal-title":"Science"},{"key":"hep31902-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"5221","DOI":"10.1128\/MCB.16.10.5221","article-title":"Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor","volume":"16","year":"1996","journal-title":"Mol Cell Biol"},{"key":"hep31902-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.immuni.2014.09.008","article-title":"HIF transcription factors, inflammation, and immunity","volume":"41","year":"2014","journal-title":"Immunity"},{"key":"hep31902-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3390\/cells5020022","article-title":"Post\u2010translational modifications of RelB NF\u2010\u03baB subunit and associated functions","volume":"5","year":"2016","journal-title":"Cells"},{"key":"hep31902-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.celrep.2014.07.028","article-title":"Nontranscriptional role of Hif\u20101\u03b1 in activation of \u03b3\u2010secretase and notch signaling in breast cancer","volume":"8","year":"2014","journal-title":"Cell Rep"},{"key":"hep31902-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11912-019-0752-z","article-title":"HIF inhibitors: status of current clinical development","volume":"21","year":"2019","journal-title":"Curr Oncol Rep"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31902","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31902","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31902","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:09:42Z","timestamp":1756076982000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31902"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,15]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31902","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,15]]},"assertion":[{"value":"2021-01-23","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-30","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}