Multi-Step Regulation of Interferon Induction by Hepatitis C Virus
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REVIEW
Multi-Step Regulation of Interferon Induction by Hepatitis C Virus Hiroyuki Oshiumi • Kenji Funami • Hussein H. Aly • Misako Matsumoto Tsukasa Seya
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Received: 30 June 2012 / Accepted: 20 December 2012 Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis
MAVS has been identified as the adaptor for RIG-I and MDA5 by four independent groups, and then also known as IPS-1, Cardif or VISA (Kawai and Akira 2009). TICAM-1 has been identified as the adaptor for TLR3 and TLR4 by two independent groups, and thus also described as TRIF (Oshiumi et al. 2003). In accordance with the HUGO Gene Nomenclature Committee-approved nomenclature, here we refer to these adaptor molecules as MAVS and TICAM-1, respectively. H. Oshiumi K. Funami H. H. Aly M. Matsumoto T. Seya (&) Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita, Sapporo 060-8638, Japan e-mail: [email protected]
through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy. Keywords Hepatitis C virus TLR3 TICAM-1 (TRIF) MAVS (IPS-1, Cardif, VISA) Interferon-inducing pathway Double-stranded RNA Abbreviations BMDC Bone marrow-derived dendritic cells CTL Cytotoxic T lymphocytes DAMP Damage-associated molecular pattern DC Dendritic cell dsRNA Double-stranded RNA IFN Interferon LD Lipid droplet MAM Mitochondrial-associated endoplasmic reticulum membranes MAVS Mitochondrial antiviral signalin
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