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Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes
  1. Barbara Testoni1,2,3,
  2. David Durantel1,2,
  3. Fanny Lebossé1,2,3,
  4. Judith Fresquet1,2,
  5. François Helle4,
  6. Francesco Negro5,
  7. Maria Francesca Donato6,
  8. Massimo Levrero7,8,9,
  9. Fabien Zoulim1,2,3,10
  1. 1INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France
  2. 2University of Lyon, UCBL, UMR_S1052, Lyon, France
  3. 3Hospices Civils de Lyon (HCL), Lyon, France
  4. 4EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France
  5. 5Division of Gastroenterology and Hepatology and of Clinical Pathology, University Hospitals, Geneva 4, Switzerland
  6. 6IRCSS Foundation Ca’ Granda, Maggiore Hospital Policlinico and University of Milan, Milan, Italy
  7. 7Department of Internal Medicine (DMISM) and the IIT-CNLS, Sapienza University of Rome, Rome, Italy
  8. 8EAL INSERM U785, Villejuif, France
  9. 9EAL INSERM U785, Rome, Italy
  10. 10Institut Universitaire de France (IUF), Paris, France
  1. Correspondence to Professor Fabien Zoulim, Centre de Recherche en Cancérologie de Lyon (CRCL), UMR_INSERM 1052-CNRS 5286, 151, cours Albert Thomas, Lyon 69424, CEDEX 03, France; fabien.zoulim{at}inserm.fr

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.

  • HEPATITIS C
  • INTERFERON
  • CHRONIC VIRAL HEPATITIS
  • GENE REGULATION

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