Hepatitis C virus (HCV) infects an estimated 3% of the world's population, and is a significant cause of liver disease. The interactions that occur between HCV proteins, cellular proteins and signal transduction machinery have a significant influence on virus replication, persistence, pathogenesis, and the outcome of antiviral therapy. Mutations in HCV proteins correlate with clinical responses to IFN therapy, and affect HCV replication in vivo and in vitro. HCV proteins also inhibit the antiviral actions of interferon (IFN). We have found that the HCV NS5A protein induces the pro-inflammatory CXC chemokine, interleukin 8 (IL-8), which is associated with inhibition of the IFN system. The in vivo significance of this finding is shown by elevated IL-8 levels in persons with chronic hepatitis C. In the HCV replicon system, we have also found that HCV replication is associated with increased production of IL-8 and attenuated IFN-induced transcriptional responses. Furthermore, exogenous IL-8 stimulates HCV protein production in HCV replicons. In this proposal, we hypothesize that HCV induced IL-8 inhibits the antiviral actions of IFN, promotes HCV replication, and contributes to HCV pathogenesis. To address this hypothesis, we propose 2 specific aims (SA) to determine the mechanisms of HCV induction of IL-8, and to determine the mechanisms of IL-8's anti-IFN activity. SA1 will focus on HCV induction of IL-8 via both transcriptional activation of the IL-8 promoter and stabilization of IL-8 mRNA. SA2 will focus on IL-8 mediated inhibition of the IFN-induced 2'-5' oligoadenylate synthetase/RNase L system, as well as cross-talk between IL-8 induced mitogen activated protein (MAP) kinases and IFN induced STAT-JAK pathways. The characterization of a new mechanism for modulation of the IFN system by a chemokine may be relevant to pathogenesis of chronic hepatitis C and many other viral and non-viral diseases. Moreover, IL-8 or its receptors may prove to be suitable targets for therapeutic intervention in chronic hepatitis C.
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