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Abstract Details
Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms
J Hepatol. 2023 Jan 23;S0168-8278(23)00016-8. doi: 10.1016/j.jhep.2023.01.005.Online ahead of print.
1CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France. Electronic address: julie.lucifora@inserm.fr.
2INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
3CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France.
4INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France.
5Gilead Sciences, Inc., Foster City, CA, USA.
6CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
7Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
8Centre Léon Bérard (CLB), INSERM, U1032, Lyon, France.
9Service de chirurgie générale et oncologique, Hôpital Lyon Sud, Hospices Civils de Lyon Et CICLY, EA3738, université Lyon 1.
10Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France.
11Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.
12INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.
13Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Gravendijkwal 230, Rotterdam, The Netherlands.
Abstract
Background & aims: Chronic co-infection with hepatitis B and D viruses (HBV and HDV) leads to the most aggressive form of chronic viral hepatitis. Here, we aimed at elucidating the molecular mechanisms leading to the interference of HDV on HBV observed in most co-infected patients.
Methods: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-seq analyses, as well as RNA synthesis, stability and association assays.
Results: Transcriptomic analyses in cell culture and mouse models of co-infection allowed to define the HDV-induced signature mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in HDV-HBV chronically infected patients but not in cells only expressing the HDV antigens (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNAs synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNAs and HDAg are associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as hepatitis C virus (HCV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Conclusions: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect RNA production of its helper virus. Exploiting these finding could pave the way to the development of new therapeutic strategies against HBV.
Impact and implications: Although, the molecular mechanisms remained unexplored, it was known for long that despite its dependency, HDV decreased HBV viremia in patients. Here, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNAs metabolism and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way to the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNAs and the HDV-induced modulation signature may allow to the draw correlation withthe responsiveness to IFN alpha treatment and thereby ultimately help in the management of HBV/HDV co-infected patients.