Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms

Julie Lucifora*, Dulce Alfaiate, Caroline Pons, Maud Michelet, Ricardo Ramirez, Floriane Fusil, Fouzia Amirache, Axel Rossi, Anne Flore Legrand, Emilie Charles, Serena Vegna, Rayan Farhat, Michel Rivoire, Guillaume Passot, Nicolas Gadot, Barbara Testoni, Charlotte Bach, Thomas F. Baumert, Anastasia Hyrina, Rudolf K. BeranFabien Zoulim, Andre Boonstra, Hildegard Büning, Eloi R. Verrier, François Loïc Cosset, Simon P. Fletcher, Anna Salvetti, David Durantel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

Background & Aims: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected 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-sequencing analyses, as well as RNA synthesis, stability and association assays. Results: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or 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 the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. Impact and implications: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.

Original languageEnglish
Pages (from-to)958-970
Number of pages13
JournalJournal of Hepatology
Volume78
Issue number5
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
This work was supported by grants from the ANRS (French national agency for research on AIDS and viral hepatitis, ( CSS12, ECTZ33708, ECTZ102776, ECTZ104527, ECTZ119828, ECTZ123278, ECTZ73912 & ECTZ77934 ) as well as financial support of INSERM. DA was supported by PhD scholarships from Fundação Calouste Gulbenkian and Fundação para a Ciência e a Tecnologia. JL received an award from the Gilead Sciences International Research Scholars Program in Liver Disease. EV and TB received a grant from ANR/FRM for work on SARS-Cov2 (Fondation pour la Recherche Médicale, grant TargEnt). TFB acknowledges funding through ERC AdG 671231 and ANR-IHU TheraHCC2 IHU201901299 and Inserm Plan Cancer. This work has been published under the framework of the LabEx DevWeCan and LABEX [ANR-10-LABX-0028_HEPSYS] and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the future program.

Publisher Copyright:
© 2023 European Association for the Study of the Liver

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