Barbara Testoni1, David Durantel2, Fanny Lebossé1, Judith Fresquet2, François Helle3, Francesco Negro4, Maria Francesca Donato5, Massimo Levrero6, Fabien Zoulim7. 1. 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. 2. INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France. 3. EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France. 4. Division of Gastroenterology and Hepatology and of Clinical Pathology, University Hospitals, Geneva 4, Switzerland. 5. IRCSS Foundation Ca' Granda, Maggiore Hospital Policlinico and University of Milan, Milan, Italy. 6. 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. 7. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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