Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence
Background and Aims Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chroni...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2021-10, Vol.74 (4), p.1766-1781 |
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| creator | Riedl, Tobias Faure‐Dupuy, Suzanne Rolland, Maude Schuehle, Svenja Hizir, Zohier Calderazzo, Silvia Zhuang, Xiaodong Wettengel, Jochen Lopez, Martin Alexander Barnault, Romain Mirakaj, Valbona Prokosch, Sandra Heide, Danijela Leuchtenberger, Corinna Schneider, Martin Heßling, Bernd Stottmeier, Benjamin Wessbecher, Isabel M. Schirmacher, Peter McKeating, Jane A Protzer, Ulrike Durantel, David Lucifora, Julie Dejardin, Emmanuel Heikenwalder, Mathias |
| description | Background and Aims
Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.
Approach and Results
We addressed whether HIF1α interferes with immune‐mediated 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 in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.
Conclusions
In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies. |
| doi_str_mv | 10.1002/hep.31902 |
| format | Article |
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Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.
Approach and Results
We addressed whether HIF1α interferes with immune‐mediated 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 in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.
Conclusions
In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.31902</identifier><identifier>PMID: 33991110</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Amino Acids, Dicarboxylic - pharmacology ; Animals ; Apolipoprotein B ; Cell Line ; Chromatin ; Circular DNA ; Cytidine deaminase ; Cytidine Deaminase - genetics ; Cytidine Deaminase - metabolism ; DNA, Circular - metabolism ; Down-Regulation ; Gene Knockdown Techniques ; Hepatitis B ; Hepatitis B virus ; Hepatitis B, Chronic - genetics ; Hepatitis B, Chronic - metabolism ; Hepatitis B, Chronic - virology ; Hepatology ; Humans ; Hybridization ; Hypoxia ; Hypoxia - genetics ; Hypoxia - metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Immune response ; Immunoblotting ; Immunocytochemistry ; Immunohistochemistry ; Immunoprecipitation ; Liver ; Liver - metabolism ; Lymphotoxin beta Receptor - agonists ; Mass spectroscopy ; Mice ; Microbial Viability ; Minor Histocompatibility Antigens - genetics ; Minor Histocompatibility Antigens - metabolism ; mRNA ; Oxygenation ; RelB protein ; RNA editing ; RNA, Messenger - metabolism ; Survival ; Transcription Factor RelB - drug effects ; Transcription Factor RelB - genetics ; Transcription Factor RelB - metabolism</subject><ispartof>Hepatology (Baltimore, Md.), 2021-10, Vol.74 (4), p.1766-1781</ispartof><rights>2021 The Authors. published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases</rights><rights>2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4542-29abb385e2af02f64c99bf3456394f36cb4d26721364c237c725ff92b8dc1bd93</citedby><cites>FETCH-LOGICAL-c4542-29abb385e2af02f64c99bf3456394f36cb4d26721364c237c725ff92b8dc1bd93</cites><orcidid>0000-0002-8858-8915 ; 0000-0003-0482-7809 ; 0000-0003-4855-1242 ; 0000-0001-7898-6795 ; 0000-0001-5618-2817 ; 0000-0002-9421-1911 ; 0000-0002-9226-3419 ; 0000-0002-3135-2274 ; 0000-0003-3236-4442</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.31902$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.31902$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33991110$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Riedl, Tobias</creatorcontrib><creatorcontrib>Faure‐Dupuy, Suzanne</creatorcontrib><creatorcontrib>Rolland, Maude</creatorcontrib><creatorcontrib>Schuehle, Svenja</creatorcontrib><creatorcontrib>Hizir, Zohier</creatorcontrib><creatorcontrib>Calderazzo, Silvia</creatorcontrib><creatorcontrib>Zhuang, Xiaodong</creatorcontrib><creatorcontrib>Wettengel, Jochen</creatorcontrib><creatorcontrib>Lopez, Martin Alexander</creatorcontrib><creatorcontrib>Barnault, Romain</creatorcontrib><creatorcontrib>Mirakaj, Valbona</creatorcontrib><creatorcontrib>Prokosch, Sandra</creatorcontrib><creatorcontrib>Heide, Danijela</creatorcontrib><creatorcontrib>Leuchtenberger, Corinna</creatorcontrib><creatorcontrib>Schneider, Martin</creatorcontrib><creatorcontrib>Heßling, Bernd</creatorcontrib><creatorcontrib>Stottmeier, Benjamin</creatorcontrib><creatorcontrib>Wessbecher, Isabel M.</creatorcontrib><creatorcontrib>Schirmacher, Peter</creatorcontrib><creatorcontrib>McKeating, Jane A</creatorcontrib><creatorcontrib>Protzer, Ulrike</creatorcontrib><creatorcontrib>Durantel, David</creatorcontrib><creatorcontrib>Lucifora, Julie</creatorcontrib><creatorcontrib>Dejardin, Emmanuel</creatorcontrib><creatorcontrib>Heikenwalder, Mathias</creatorcontrib><title>Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Background and Aims
Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.
Approach and Results
We addressed whether HIF1α interferes with immune‐mediated 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 in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.
Conclusions
In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.</description><subject>Amino Acids, Dicarboxylic - pharmacology</subject><subject>Animals</subject><subject>Apolipoprotein B</subject><subject>Cell Line</subject><subject>Chromatin</subject><subject>Circular DNA</subject><subject>Cytidine deaminase</subject><subject>Cytidine Deaminase - genetics</subject><subject>Cytidine Deaminase - metabolism</subject><subject>DNA, Circular - metabolism</subject><subject>Down-Regulation</subject><subject>Gene Knockdown Techniques</subject><subject>Hepatitis B</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B, Chronic - genetics</subject><subject>Hepatitis B, Chronic - metabolism</subject><subject>Hepatitis B, Chronic - virology</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Hybridization</subject><subject>Hypoxia</subject><subject>Hypoxia - genetics</subject><subject>Hypoxia - metabolism</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</subject><subject>Immune response</subject><subject>Immunoblotting</subject><subject>Immunocytochemistry</subject><subject>Immunohistochemistry</subject><subject>Immunoprecipitation</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Lymphotoxin beta Receptor - agonists</subject><subject>Mass spectroscopy</subject><subject>Mice</subject><subject>Microbial Viability</subject><subject>Minor Histocompatibility Antigens - genetics</subject><subject>Minor Histocompatibility Antigens - metabolism</subject><subject>mRNA</subject><subject>Oxygenation</subject><subject>RelB protein</subject><subject>RNA editing</subject><subject>RNA, Messenger - metabolism</subject><subject>Survival</subject><subject>Transcription Factor RelB - drug effects</subject><subject>Transcription Factor RelB - genetics</subject><subject>Transcription Factor RelB - metabolism</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp10UFv0zAUB3ALMbFucOALIEtc4JDVfk7i-tiWjk4aWoWAa-Q4L8yTG2d2otLbPgIS35BPMm8dHJA4Wdb7vb8s_wl5zdkZZwym19ifCa4YPCMTXoDMhCjYczJhIFmmuFDH5CTGG8aYymH2ghwLoRTnnE1IWO97_8Pq33c_L7pmNLZ2SM-1GXygnM5df51Gvz5hY_WADf2MbjGdb64Wq6VY0A9-16XFgN9Hpwfru7Tg_C7SNfbpPthIF_SbDWOkGwzRxgE7gy_JUatdxFdP5yn5er76slxnl1cfL5bzy8zkRQ4ZKF3XYlYg6JZBW-ZGqboVeVEKlbeiNHXeQCmBizQCIY2Eom0V1LPG8LpR4pS8O-T2wd-OGIdqa6NB53SHfowVFDDjUpayTPTtP_TGj6FLr0tKFkpIJSGp9wdlgo8xYFv1wW512FecVQ9FVKmI6rGIZN88JY71Fpu_8s_PJzA9gJ11uP9_UrVebQ6R9_xlkx4</recordid><startdate>202110</startdate><enddate>202110</enddate><creator>Riedl, Tobias</creator><creator>Faure‐Dupuy, Suzanne</creator><creator>Rolland, Maude</creator><creator>Schuehle, Svenja</creator><creator>Hizir, Zohier</creator><creator>Calderazzo, Silvia</creator><creator>Zhuang, Xiaodong</creator><creator>Wettengel, Jochen</creator><creator>Lopez, Martin Alexander</creator><creator>Barnault, Romain</creator><creator>Mirakaj, Valbona</creator><creator>Prokosch, Sandra</creator><creator>Heide, Danijela</creator><creator>Leuchtenberger, Corinna</creator><creator>Schneider, Martin</creator><creator>Heßling, Bernd</creator><creator>Stottmeier, Benjamin</creator><creator>Wessbecher, Isabel M.</creator><creator>Schirmacher, Peter</creator><creator>McKeating, Jane A</creator><creator>Protzer, Ulrike</creator><creator>Durantel, David</creator><creator>Lucifora, Julie</creator><creator>Dejardin, Emmanuel</creator><creator>Heikenwalder, Mathias</creator><general>Wolters Kluwer Health, Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8858-8915</orcidid><orcidid>https://orcid.org/0000-0003-0482-7809</orcidid><orcidid>https://orcid.org/0000-0003-4855-1242</orcidid><orcidid>https://orcid.org/0000-0001-7898-6795</orcidid><orcidid>https://orcid.org/0000-0001-5618-2817</orcidid><orcidid>https://orcid.org/0000-0002-9421-1911</orcidid><orcidid>https://orcid.org/0000-0002-9226-3419</orcidid><orcidid>https://orcid.org/0000-0002-3135-2274</orcidid><orcidid>https://orcid.org/0000-0003-3236-4442</orcidid></search><sort><creationdate>202110</creationdate><title>Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence</title><author>Riedl, Tobias ; Faure‐Dupuy, Suzanne ; Rolland, Maude ; Schuehle, Svenja ; Hizir, Zohier ; Calderazzo, Silvia ; Zhuang, Xiaodong ; Wettengel, Jochen ; Lopez, Martin Alexander ; Barnault, Romain ; Mirakaj, Valbona ; Prokosch, Sandra ; Heide, Danijela ; Leuchtenberger, Corinna ; Schneider, Martin ; Heßling, Bernd ; Stottmeier, Benjamin ; Wessbecher, Isabel M. ; Schirmacher, Peter ; McKeating, Jane A ; Protzer, Ulrike ; Durantel, David ; Lucifora, Julie ; Dejardin, Emmanuel ; Heikenwalder, Mathias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4542-29abb385e2af02f64c99bf3456394f36cb4d26721364c237c725ff92b8dc1bd93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amino Acids, Dicarboxylic - pharmacology</topic><topic>Animals</topic><topic>Apolipoprotein B</topic><topic>Cell Line</topic><topic>Chromatin</topic><topic>Circular DNA</topic><topic>Cytidine deaminase</topic><topic>Cytidine Deaminase - genetics</topic><topic>Cytidine Deaminase - metabolism</topic><topic>DNA, Circular - metabolism</topic><topic>Down-Regulation</topic><topic>Gene Knockdown Techniques</topic><topic>Hepatitis B</topic><topic>Hepatitis B virus</topic><topic>Hepatitis B, Chronic - genetics</topic><topic>Hepatitis B, Chronic - metabolism</topic><topic>Hepatitis B, Chronic - virology</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Hybridization</topic><topic>Hypoxia</topic><topic>Hypoxia - genetics</topic><topic>Hypoxia - metabolism</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</topic><topic>Immune response</topic><topic>Immunoblotting</topic><topic>Immunocytochemistry</topic><topic>Immunohistochemistry</topic><topic>Immunoprecipitation</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Lymphotoxin beta Receptor - agonists</topic><topic>Mass spectroscopy</topic><topic>Mice</topic><topic>Microbial Viability</topic><topic>Minor Histocompatibility Antigens - genetics</topic><topic>Minor Histocompatibility Antigens - metabolism</topic><topic>mRNA</topic><topic>Oxygenation</topic><topic>RelB protein</topic><topic>RNA editing</topic><topic>RNA, Messenger - metabolism</topic><topic>Survival</topic><topic>Transcription Factor RelB - drug effects</topic><topic>Transcription Factor RelB - genetics</topic><topic>Transcription Factor RelB - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Riedl, Tobias</creatorcontrib><creatorcontrib>Faure‐Dupuy, Suzanne</creatorcontrib><creatorcontrib>Rolland, Maude</creatorcontrib><creatorcontrib>Schuehle, Svenja</creatorcontrib><creatorcontrib>Hizir, Zohier</creatorcontrib><creatorcontrib>Calderazzo, Silvia</creatorcontrib><creatorcontrib>Zhuang, Xiaodong</creatorcontrib><creatorcontrib>Wettengel, Jochen</creatorcontrib><creatorcontrib>Lopez, Martin Alexander</creatorcontrib><creatorcontrib>Barnault, Romain</creatorcontrib><creatorcontrib>Mirakaj, Valbona</creatorcontrib><creatorcontrib>Prokosch, Sandra</creatorcontrib><creatorcontrib>Heide, Danijela</creatorcontrib><creatorcontrib>Leuchtenberger, Corinna</creatorcontrib><creatorcontrib>Schneider, Martin</creatorcontrib><creatorcontrib>Heßling, Bernd</creatorcontrib><creatorcontrib>Stottmeier, Benjamin</creatorcontrib><creatorcontrib>Wessbecher, Isabel M.</creatorcontrib><creatorcontrib>Schirmacher, Peter</creatorcontrib><creatorcontrib>McKeating, Jane A</creatorcontrib><creatorcontrib>Protzer, Ulrike</creatorcontrib><creatorcontrib>Durantel, David</creatorcontrib><creatorcontrib>Lucifora, Julie</creatorcontrib><creatorcontrib>Dejardin, Emmanuel</creatorcontrib><creatorcontrib>Heikenwalder, Mathias</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Riedl, Tobias</au><au>Faure‐Dupuy, Suzanne</au><au>Rolland, Maude</au><au>Schuehle, Svenja</au><au>Hizir, Zohier</au><au>Calderazzo, Silvia</au><au>Zhuang, Xiaodong</au><au>Wettengel, Jochen</au><au>Lopez, Martin Alexander</au><au>Barnault, Romain</au><au>Mirakaj, Valbona</au><au>Prokosch, Sandra</au><au>Heide, Danijela</au><au>Leuchtenberger, Corinna</au><au>Schneider, Martin</au><au>Heßling, Bernd</au><au>Stottmeier, Benjamin</au><au>Wessbecher, Isabel M.</au><au>Schirmacher, Peter</au><au>McKeating, Jane A</au><au>Protzer, Ulrike</au><au>Durantel, David</au><au>Lucifora, Julie</au><au>Dejardin, Emmanuel</au><au>Heikenwalder, Mathias</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2021-10</date><risdate>2021</risdate><volume>74</volume><issue>4</issue><spage>1766</spage><epage>1781</epage><pages>1766-1781</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><abstract>Background and Aims
Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.
Approach and Results
We addressed whether HIF1α interferes with immune‐mediated 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 in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.
Conclusions
In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>33991110</pmid><doi>10.1002/hep.31902</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-8858-8915</orcidid><orcidid>https://orcid.org/0000-0003-0482-7809</orcidid><orcidid>https://orcid.org/0000-0003-4855-1242</orcidid><orcidid>https://orcid.org/0000-0001-7898-6795</orcidid><orcidid>https://orcid.org/0000-0001-5618-2817</orcidid><orcidid>https://orcid.org/0000-0002-9421-1911</orcidid><orcidid>https://orcid.org/0000-0002-9226-3419</orcidid><orcidid>https://orcid.org/0000-0002-3135-2274</orcidid><orcidid>https://orcid.org/0000-0003-3236-4442</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0270-9139 |
| ispartof | Hepatology (Baltimore, Md.), 2021-10, Vol.74 (4), p.1766-1781 |
| issn | 0270-9139 1527-3350 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2528177676 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Amino Acids, Dicarboxylic - pharmacology Animals Apolipoprotein B Cell Line Chromatin Circular DNA Cytidine deaminase Cytidine Deaminase - genetics Cytidine Deaminase - metabolism DNA, Circular - metabolism Down-Regulation Gene Knockdown Techniques Hepatitis B Hepatitis B virus Hepatitis B, Chronic - genetics Hepatitis B, Chronic - metabolism Hepatitis B, Chronic - virology Hepatology Humans Hybridization Hypoxia Hypoxia - genetics Hypoxia - metabolism Hypoxia-Inducible Factor 1, alpha Subunit - genetics Immune response Immunoblotting Immunocytochemistry Immunohistochemistry Immunoprecipitation Liver Liver - metabolism Lymphotoxin beta Receptor - agonists Mass spectroscopy Mice Microbial Viability Minor Histocompatibility Antigens - genetics Minor Histocompatibility Antigens - metabolism mRNA Oxygenation RelB protein RNA editing RNA, Messenger - metabolism Survival Transcription Factor RelB - drug effects Transcription Factor RelB - genetics Transcription Factor RelB - metabolism |
| title | Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T00%3A06%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hypoxia%E2%80%90Inducible%20Factor%201%20Alpha%E2%80%93Mediated%20RelB/APOBEC3B%20Down%E2%80%90regulation%20Allows%20Hepatitis%20B%20Virus%20Persistence&rft.jtitle=Hepatology%20(Baltimore,%20Md.)&rft.au=Riedl,%20Tobias&rft.date=2021-10&rft.volume=74&rft.issue=4&rft.spage=1766&rft.epage=1781&rft.pages=1766-1781&rft.issn=0270-9139&rft.eissn=1527-3350&rft_id=info:doi/10.1002/hep.31902&rft_dat=%3Cproquest_cross%3E2575937972%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2575937972&rft_id=info:pmid/33991110&rfr_iscdi=true |