Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system

Authors

  • Pantxika Bellecave,

    1. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    Search for more papers by this author
    • These authors have equally contributed to this work

  • Magdalena Sarasin-Filipowicz,

    1. Department of Biomedicine and Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
    Search for more papers by this author
    • These authors have equally contributed to this work

  • Olivier Donzé,

    1. Apotech Corporation, Epalinges, Switzerland
    Search for more papers by this author
  • Audrey Kennel,

    1. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    Search for more papers by this author
  • Jérôme Gouttenoire,

    1. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    Search for more papers by this author
  • Etienne Meylan,

    1. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
    2. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
    Search for more papers by this author
  • Luigi Terracciano,

    1. Pathology Institute, University Hospital Basel, Basel, Switzerland
    Search for more papers by this author
  • Jürg Tschopp,

    1. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
    Search for more papers by this author
  • Christoph Sarrazin,

    1. Department of Medicine I, J. W. Goethe University Hospital, Frankfurt, Germany
    Search for more papers by this author
  • Thomas Berg,

    1. Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Campus Virchow-Klinikum, Berlin, Germany
    Search for more papers by this author
  • Darius Moradpour,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    • Division of Gastroenterology and Hepatology, Centre Hospitaliser Universitaire Vaudois, Rue du Bugnon 44, CH-1011 Lausanne, Switzerland
    Search for more papers by this author
    • These authors have equally contributed to this work.

    • Fax (41)-21-314-47-18

  • Markus H. Heim

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
    • Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    Search for more papers by this author
    • These authors have equally contributed to this work.

    • Fax: (41)-61-265-53-52


  • Potential conflict of interest: Nothing to report.

Abstract

Hepatitis C virus (HCV) infection induces the endogenous interferon (IFN) system in the liver in some but not all patients with chronic hepatitis C (CHC). Patients with a pre-activated IFN system are less likely to respond to the current standard therapy with pegylated IFN-α. Mitochondrial antiviral signaling protein (MAVS) is an important adaptor molecule in a signal transduction pathway that senses viral infections and transcriptionally activates IFN-β. The HCV NS3-4A protease can cleave and thereby inactivate MAVS in vitro, and, therefore, might be crucial in determining the activation status of the IFN system in the liver of infected patients. We analyzed liver biopsies from 129 patients with CHC to investigate whether MAVS is cleaved in vivo and whether cleavage prevents the induction of the endogenous IFN system. Cleavage of MAVS was detected in 62 of the 129 samples (48%) and was more extensive in patients with a high HCV viral load. MAVS was cleaved by all HCV genotypes (GTs), but more efficiently by GTs 2 and 3 than by GTs 1 and 4. The IFN-induced Janus kinase (Jak)-signal transducer and activator of transcription protein (STAT) pathway was less frequently activated in patients with cleaved MAVS, and there was a significant inverse correlation between cleavage of MAVS and the expression level of the IFN-stimulated genes IFI44L, Viperin, IFI27, USP18, and STAT1. We conclude that the pre-activation status of the endogenous IFN system in the liver of patients with CHC is in part regulated by cleavage of MAVS. (HEPATOLOGY 2010.)

Ancillary