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

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
Document type :
Journal articles
Complete list of metadatas

https://hal-univ-lyon1.archives-ouvertes.fr/hal-01796188
Contributor : Lauriane Pillet <>
Submitted on : Saturday, May 19, 2018 - 11:34:10 AM
Last modification on : Friday, May 25, 2018 - 4:51:20 PM

Identifiers

Collections

Citation

Barbara Testoni, David Durantel, Fanny Lebossé, Judith Fresquet, François Helle, et al.. Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes. Gut, BMJ Publishing Group, 2016, 65 (4), pp.672-682. ⟨10.1136/gutjnl-2014-309011⟩. ⟨hal-01796188⟩

Share

Metrics

Record views

48