Journal article
Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes.
- Testoni B 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.
- Durantel D INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France.
- Lebossé F 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.
- Fresquet J INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France University of Lyon, UCBL, UMR_S1052, Lyon, France.
- Helle F EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
- Negro F Division of Gastroenterology and Hepatology and of Clinical Pathology, University Hospitals, Geneva 4, Switzerland.
- Donato MF IRCSS Foundation Ca' Granda, Maggiore Hospital Policlinico and University of Milan, Milan, Italy.
- Levrero M 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.
- Zoulim F 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.
- 2015-06-18
Published in:
- Gut. - 2016
CHRONIC VIRAL HEPATITIS
GENE REGULATION
HEPATITIS C
INTERFERON
Antiviral Agents
Blotting, Western
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Epigenomics
Gene Expression
Hepacivirus
Hepatitis C, Chronic
Hepatocytes
Histone-Lysine N-Methyltransferase
Humans
Immunoprecipitation
Interferon-alpha
RNA, Messenger
Real-Time Polymerase Chain Reaction
Ribavirin
Transfection
Viral Load
Virus Replication
English
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.
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1136/gutjnl-2014-309011
- PMID 26082258
- Persistent URL
- https://sonar.ch/global/documents/192361
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