Julie Lucifora, Charlotte Bach, David Durantel, Eloi R. Verrier, Ivan Hirsch, Mirjam B. Zeisel, Seung-Ae Yim, Nicolas Manel, Nathalie Pochet, Laurent Mailly, Sarah C. Durand, Thomas F. Baumert, Patrick Pessaux, Houssein El Saghire, Laura Heydmann, Vincent Turon-Lagot, Catherine Schuster, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de recherche Paris, sciences et lettres [Institut Curie, Paris], Institut Curie [Paris], Department of Genetics and Microbiology [Prague, Czech Republic] (Faculty of Science), Charles University [Prague] (CU), Department of Neurology [Cambridge, MA, USA] (Ann Romney Center for Neurologic Diseases), Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Cell Circuits Program [Cambridge, MA, USA], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Union (ERC-AdG-2014-671231- HEPCIR, EU H2020-667273-HEPCAR, EU-InfectEra HepBccc), the National Institute of Health (NIAID 1R03AI131066-01A1, NCI R21 CA209940 and NIAID U19AI123862), the Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS, 2015/1099), the Fondation ARC pour la Recherche sur le Cancer (TheraHCC IHUARC IHU201301187), GACR 17-15422S, and a PhD fellowship of the Région Alsace, France. The work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program. E.R.V. was supported by an ANRS fellowship (ECTZ50121)., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Baumert, Thomas F., Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
International audience; Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was identified as a DNA sensor. In this study, we investigated the functional role of cGAS in sensing HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss-of-function and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes, and HBV-infected human liver chimeric mice. Here, we show that cGAS is expressed in the human liver, primary human hepatocytes, and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral covalently closed circular DNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. Conclusion: HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways.