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

Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Hepatology (Impact Factor: 11.06). 04/2010; 51(4):1127-36. DOI: 10.1002/hep.23426
Source: PubMed


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.

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Available from: Thomas Berg, Sep 13, 2014
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    • "In this context, we note that both MAVS and TICAM-1 are direct targets for proteolytic degradation by the HCV-encoded NS3/4A protease [39], [40]. Related reports [39], [40], [41] suggest that the inhibitory effect of this viral protease may affect the induction of IFN-λs, particularly in HCV-infected hepatocytes. However, we observed significantly higher levels of IFN-λ expression in response to treatment with LIC-pIC, regardless of in vivo HCV infection status (Fig. 3 and data not shown), suggesting that the in vivo induction of IFN- λs by LIC-pIC treatment may not be affected by this viral protease in our experimental system. "
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    ABSTRACT: The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "It has not been investigated whether cleavage of MAVS or TRIF3 occurs in the early acute phase of HCV infection. In the chronic phase of HCV infection, cleavage of MAVS was detected in 62 out of 129 (48%) liver biopsies from patients with CHC [77]. MAVS cleavage most likely occurs in HCV infected hepatocytes, and could prevent IFN induction in those cells. "
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    • "Although circumstantial, the evidence is nonetheless notable. For example, a higher incidence of vitamin D deficiency was observed in patients with chronic hepatitis C, even those without fibrotic changes in the liver, compared to controls; second, published data indicate that hydroxylation of cholecalciferol can be inhibited or impaired by viral induction of inflammatory cytokines; third, the finding that circulating 25(OH)D levels increased after eradication of the virus [60]. "
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