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

Gut. 2016 Apr;65(4):672-82. doi: 10.1136/gutjnl-2014-309011. Epub 2015 Jun 16.


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.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Blotting, Western
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Epigenomics
  • Gene Expression / drug effects
  • Hepacivirus / drug effects
  • Hepatitis C, Chronic
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Immunoprecipitation
  • Interferon-alpha / genetics*
  • Interferon-alpha / pharmacology*
  • RNA, Messenger / drug effects
  • Real-Time Polymerase Chain Reaction
  • Ribavirin / pharmacology*
  • Transfection
  • Viral Load
  • Virus Replication / drug effects


  • Antiviral Agents
  • Interferon-alpha
  • RNA, Messenger
  • Ribavirin
  • G9a protein, mouse
  • Histone-Lysine N-Methyltransferase