title: Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France Hospices Civils de Lyon (HCL), Lyon, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Testoni
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France Hospices Civils de Lyon (HCL), Lyon, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lebossé
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Fresquet
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: François
authors.initials: F
authors.lastname: Helle
authors.affiliation: Division of Gastroenterology and Hepatology and of Clinical Pathology, University Hospitals, Geneva 4, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.affiliation: IRCSS Foundation Ca' Granda, Maggiore Hospital Policlinico and University of Milan, Milan, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Donato
authors.affiliation: Department of Internal Medicine (DMISM) and the IIT-CNLS, Sapienza University of Rome, Rome, Italy EAL INSERM U785, Villejuif, France EAL INSERM U785, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France Hospices Civils de Lyon (HCL), Lyon, France Institut Universitaire de France (IUF), Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D057890:Epigenomics; D015870:Gene Expression / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000235:genetics* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology*; D014162:Transfection; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012333:RNA, Messenger; D012254:Ribavirin; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: CHRONIC VIRAL HEPATITIS; GENE REGULATION; HEPATITIS C; INTERFERON