Hepatitis C virus (HCV) efficiently establishes persistent infection by a mechanism that is poorly understood. HCV infection induces IFN in chronically infected individuals, but fails to clear virus. In addition, IFN based antiviral therapy fails in about half of those patients treated. High HCV genetic variation occurring in genes that counteract the type 1 IFN response correlate with successful therapy. Modest neutralizing antibody is generated to HCV infected humans and the can be augmented in vitro by the addition of complement. Based on these observations, we hypothesize that HCV interacts with cellular proteins to promote escape from innate immunity. Therefore, we are evaluating the molecular interactions between HCV and its genetic variants with key players of the innate immune response.