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.
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-alpha. Mitochondrial antiviral signaling protein (MAVS) is an important adaptor molecule in a signal transduction pathway that senses viral infections and transcriptionally activates IFN-beta. 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.
Bellecave
Pantxika
P
Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Sarasin-Filipowicz
Magdalena
M
Donzé
Olivier
O
Kennel
Audrey
A
Gouttenoire
Jérôme
J
Meylan
Etienne
E
Terracciano
Luigi
L
Tschopp
Jürg
J
Sarrazin
Christoph
C
Berg
Thomas
T
Moradpour
Darius
D
Heim
Markus H
MH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D019562:Viral Load
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D007372:Interferons