Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Barbara Testoni, David Durantel, Fanny Lebossé, Judith Fresquet, François Helle, Francesco Negro, Maria Francesca Donato, Massimo Levrero, Fabien Zoulim

Research output: Contribution to journalArticle

Abstract

Objectives Caveats in the understanding of ribavirin (RBV) mechanisms of action has somehow prevented the development of better analogues able to further improve its therapeutic contribution in interferon (IFN)-based and direct antiviral agent-based regimens for chronic HCV or other indications. Here, we describe a new mechanism by which RBV modulates IFN-stimulated genes (ISGs) and contributes to restore hepatic immune responsiveness. Design RBV effect on ISG expression was monitored in vitro and in vivo, that is, in non-transformed hepatocytes and in the liver of RBV mono-treated patients, respectively. Modulation of histone modifications and recruitment of histone-modifying enzymes at target promoters was analysed by chromatin immunoprecipitation in RBV-treated primary human hepatocytes and in patients' liver biopsies. Results RBV decreases the mRNA levels of several abnormally preactivated ISGs in patients with HCV, who are non-responders to IFN therapy. RBV increases G9a histone methyltransferase recruitment and histone-H3 lysine-9 dimethylation/trimethylation at selected ISG promoters in vitro and in vivo. G9a pharmacological blockade abolishes RBV-induced ISG downregulation and severely impairs RBV ability to potentiate IFN antiviral action and induction of ISGs following HCV infection of primary human hepatocytes. Conclusions RBV-induced epigenetic changes, leading to decreased ISG expression, restore an IFN-responsive hepatic environment in patients with HCV, which may also prove useful in IFN-free regimens.

Original languageEnglish
Pages (from-to)672-682
Number of pages11
JournalGut
Volume65
Issue number4
DOIs
Publication statusPublished - 2016

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ASJC Scopus subject areas

  • Gastroenterology

Cite this

Testoni, B., Durantel, D., Lebossé, F., Fresquet, J., Helle, F., Negro, F., Donato, M. F., Levrero, M., & Zoulim, F. (2016). Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes. Gut, 65(4), 672-682. https://doi.org/10.1136/gutjnl-2014-309011