Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes. Issue 4 (16th June 2015)

• Record Type: Journal Article
• Authors: Testoni, Barbara; Durantel, David; Lebossé, Fanny; Fresquet, Judith; Helle, François; Negro, Francesco; Donato, Maria Francesca; Levrero, Massimo; Zoulim, Fabien
• Is Part Of: Gut. Volume 65:Issue 4(2016)
• Page Start: 672
• Page End: 682
• Publication Date: 2015-06-16
• Subjects: HEPATITIS C -- INTERFERON -- CHRONIC VIRAL HEPATITIS -- GENE REGULATION; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2014-309011
• Languages: English
• ISSNs: 0017-5749

Abstract

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.