Hepatitis C Virus: The Role of Molecular Mimicry in Response to Interferon (IFN) Treatment

Abstract

Chronic hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease worldwide. In order for HCV to persist, the virus must escape immune recognition or inhibit the host immune response. The NS5A protein contains the interferon sensitivity determining region (ISDR) and is able to repress dsRNA-dependent protein kinase (PKR) thus influencing the response to interferon (IFN) therapy. Moreover, patients who respond to IFN 30 therapy have stronger antibody reactivity against the NS5A compared to IFN non-responders. Therefore, given the possible role for the ISDR in IFN resistance and differential antibody reactivity, we propose that variation in ISDR may be involved in viral immune escape and development of persistent HCV infection employing aspects of host mimicry. In this study, pre-treatment samples obtained from HCV infected patients were used to investigate the effect of different NS5A ISDR variants on the IFN antiviral response and their involvement in immune evasion. We have identified NS5A as a homologue of the variable region of immunoglobulins (Ig). The IFN resistant genotypes had higher levels of similarity to Ig compared to IFN sensitive genotypes. Expression of NS5A-6003 (HCV genotype 1b) and NS5A-6074 (HCV genotype 2a) was able to rescue Vesicular Stomatitis Virus (VSV) from IFN inhibition and restore luciferase activity. We have observed a correlation between Ig-like NS5A structure and also antibody response with the outcome of IFN treatment.