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.
    PLoS ONE 03/2013; 8(3):e59611. DOI:10.1371/journal.pone.0059611 · 3.23 Impact Factor
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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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    ABSTRACT: Hepatitis C virus (HCV) infections become chronic in the majority of infected individuals, and chronic hepatitis C (CHC) can lead to cirrhosis and hepatocellular carcinoma. The innate immune system is central to host-virus interactions during the entire natural course of the disease. The HCV NS3/4A protease efficiently cleaves and inactivates two important signaling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce interferons (IFNs), i.e., mitochondrial antiviral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). Despite this viral escape mechanism, the innate immune system strongly reacts to HCV within the first days after infection. The sensory pathways, the type(s) of IFNs involved and the cellular source of IFNs are largely unknown. After 4–8 weeks, HCV specific T cells are recruited to the liver. IFN-γ-stimulated genes get strongly expressed in the liver. In about 30% of patients, the virus is eliminated during the acute phase of the infection by T cell-mediated antiviral mechanisms. In the remaining 70% of patients, HCV persists for decades. During this phase, T cell-derived IFN-γ cannot be detected any more in liver biopsies. Instead, in about half of the patients, hundreds of type I or III IFN-stimulated genes become again strongly expressed. However, this innate immune reaction is ineffective against HCV. Moreover, patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The viral escape mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cells with refractory IFN signal transduction pathways or to cell compartments that are not accessible to antiviral IFN-stimulated effector systems. Recently, genetic variations near the IL28B (IFN-λ3) were found to be strongly associated with spontaneous clearance of HCV and response to treatment with PegIFN-α and ribavirin. The finding supports a central role of the innate immune response in host-viral interactions. The signaling pathways that link genetic variants of IL28B with immune answers to HCV remain to be elucidated. The present review article attempts to summarize current knowledge of some central aspects of the interactions of HCV with the innate immune system.
    Journal of Hepatology 10/2012; 58(3). DOI:10.1016/j.jhep.2012.10.005 · 11.34 Impact Factor
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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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    ABSTRACT: Dynamic interactions between microorganism and host have evolved in such a way that while microbial pathogens are the cause of many human infections, a symbiotic relationship is also known to exist. Another important anomaly is that exposure to pathogenic organisms does not necessarily result in development of clinical disease. The latter conclusion infers that susceptibility to infectious disease can be modified by host-related factors. Arguably the two most prominent factors are genetic variability and immunologic status of the exposed individual. Because of the Human Genome and the HapMap projects, developments in genotyping technology have brought the possibility of identifying associations between specific genetic alterations and common diseases closer to reality. In addition, a growing body of evidence suggests vitamin D has an important contributory role in the antimicrobial pathway.
    06/2012; 2012:129516. DOI:10.6064/2012/129516
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