Unmasking a silent killer : uncovering the mechanism of Hepatitis C virus protein NS5A-mediated inhibition of the innate immune response

Abstract

Hepatitis C Virus (HCV) is a human liver pathogen. In the host its infection leads to acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. This positive stranded RNA virus is extremely efficient in establishing persistent infection by escaping immune detection by hindering the host immune responses. An important component of the host?s innate immune response in viral infection is the production of type I interferons (IFNs). Typically, viral infection induces the synthesis and secretion of interferon a/? (IFN a/?) by the infected cell, which in turn activates signaling pathways leading to the establishment of an antiviral state in the cell. This raises the question of how HCV circumvents the antiviral immune responses of host cells. Previous studies have shown that HCV nonstructural protein NS3/4A interferes with the activation of signaling pathways that leads to the activation of the IFN?. Our lab has identified another HCV protein, NS5A, that also interferes with host antiviral signaling independent of the NS3/4A-mediated inhibition of the host antiviral response. Activation of IFN? gene expression involves the activation of three transcription factors (ATF-2, IRF3/7 and NF-?B) and the formation of an enhanceosome on the promoter. To investigate the influence of HCV NS5A on innate immunity, we study the effect of NS5A over-expression on Sendai Virus (SV)-mediated IFN? gene induction via qPCR and reporter gene assay. We have identified NS5A to be a potent inhibitor of the host innate immune system, possibly through inhibition of IRF3 activation. We are currently investigating the effect of NS5A on transcription factor activation. NS5A inhibition of IFN? induction, may be another factor contributing to the persistence of HCV in the host, and may play a key role in designing therapies for the treatment of HCV infection