The Role of Interferon Stimlated Genes in Resistance and Immunity to Hepatitis C Virus Infection

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2009-01-15

Authors

Erickson, Andrea Kaup

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Abstract

Hepatitis C Virus (HCV) is a global public health issue with 170 million people chronically infected. The only approved treatment for HCV infection is interferon-alpha based therapy, resulting in viral clearance in approximately fifty percent of patients treated. Interferon therapy mimics endogenous type I interferon signaling, which plays a crucial role in the innate antiviral response through the regulation of interferon stimulated genes (ISGs). ISGs encode antiviral effector proteins that limit viral replication and spread. Hundreds of ISGs have been identified in the liver of HCV patients who respond to IFN therapy; however the functions of most these genes are not known. In order to better understand the molecular mechanisms of the IFN antiviral response, studies were initiated to identify and characterize the functions of novel ISGs involved in controlling HCV infection. To determine the most effective IFN for these studies, the antiviral activity and functional effects of three distinct type I IFN subtypes were evaluated. Consensus interferon demonstrated maximal suppression of HCV replication, correlating with enhanced IFN signaling and ISG induction. A functional genomics analysis of IFN treated primary hepatocytes resulted in the identification of eighty-six ISGs differentially induced by consensus interferon. Future evaluations of the role of these genes in HCV outcome, using integrated approaches as described here, will be invaluable in further defining the molecular mechanisms of the innate IFN antiviral response. Although a number of ISGs have recently been reported to function as antiviral proteins in vitro, these studies did not validate the involvement of these genes in innate immunity or disease outcome. In order to evaluate the biological relevance of a genetic variant of the oligoadenylate synthetase 1 (OAS1) gene in resistance to HCV infection, an integrated approach of epidemiology, molecular genetics, and functional biology was used. Genetic and epidemiologic analyses identified a single-base mutation in OAS1 that associates with HCV resistance in individuals with a high-risk for HCV infection. Functional studies of the resulting OAS1 variant demonstrated altered biological activities of the protein, resulting in enhanced suppression of HCV genotype 1a and 2a infectious clones. Furthermore, a recombinant drug form of the OAS1 variant demonstrated broad antiviral activity, suggesting great promise for this protein as a therapeutic for HCV infection.

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