Tobias Riedl1,2, Suzanne Faure-Dupuy1,3, Maude Rolland4, Emmanuel Dejardin4, Mathias Heikenwalder1,3, Svenja Schuehle1,2, Zohier Hizir4, Silvia Calderazzo5, Xiaodong Zhuang6,7, Jochen Wettengel8, Martin Alexander Lopez4, Romain Barnault9, Valbona Mirakaj9, Sandra Prokosch1, Danijela Heide1, Corinna Leuchtenberger1, Martin Schneider10, Bernd Heßling10, Benjamin Stottmeier11,12, Isabel M Wessbecher11,13, Peter Schirmacher11,13, Jane A McKeating6,7, Ulrike Protzer8, David Durantel14, Julie Lucifora14. 1. Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. 2. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 3. Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany. 4. Laboratory of Molecular Immunology and Signal Transduction, GIGA-Institute, University of Liège, Liège, Belgium. 5. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. 7. Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, United Kingdom. 8. Institute of Virology, Helmholtz Zentrum München, Munich, Germany. 9. Departement of Anesthesiology and Intensive Care Medicine, Molecular Intensive Care Medicine, University Hospital Tübingen, Eberhard-Karls-University, Tuebingen, Germany. 10. Mass Spectrometry Based Protein Analysis Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. 11. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 12. German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. 13. Tissue Bank of the German Center for Infection Research (DZIF), Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 14. INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard (CLB), Lyon, France.
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.
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.
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