Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. HIV coinfection and race are associated with impaired response to IFN-a based HCV therapy (Peg-IFN-a/ribavirin and Peg-IFN-a/ribavirin/protease inhibitor). Mechanisms underlying these associations are not clear, though IL28B genotype likely accounts for a portion of the racial association. IFN-a has many effects on cell function, including direct natural killer (NK) cell activation. NK cell inhibitory receptor KIR2DL3 in combination with its weaker binding ligand (HLA-C1) are associated with clearance of acute HCV infection, while the activating receptor KIR3DS1 and the appropriate ligand (HLA-Bw4-80ile) are associated with slower progression of HIV infection. NK cell KIRs are also associated with response to IFN-a based HCV therapy. NK cells therefore likely play a role in control of both HCV and HIV infection. Our new data indicate CD16+56- NK subset IFN-aR expression level regulates IFN-a signaling, predicts response to IFN-a based HCV therapy, and is racially and IL28B genotype associated. Plasmacytoid dendritic cells (pDC) produce IFN-a during viral infection, and directly activate NK cells. Lower pDC and NK subset frequency and function are present during HIV infection, including impaired NK response to IFN-a. Our data indicate impairment in both NK and pDC function contributes to impaired pDC-NK interactions during HIV infection. Altered pDC numbers and function are also present during HCV infection. Whether defects present in each infection collaborate in impairing HCV-HIV co- infected host ability to control of HCV infection is not known. Additionally, whether IL28B genotype underlies racially disparate NK IFN-aR expression level and consequent signaling is unclear. We propose a novel model that lends mechanistic understanding of IL-28B, race and HIV mediated effects on IFN-a based HCV therapy response. Investigation of this model is intended to provide a foundation for improved therapy options in difficult to treat HCV infected subgroups (HIV co-infection and African descent), and a broader understanding of NK mediated control of chronic viral infection. We will in Aim 1 Determine the effect of IL28B, race, and HIV infection on NK and pDC-NK mediated control of HCV replication in vitro. In Aim 2 we will determine whether IL28B associated IFN-aR expression and IFN-a dependent NK control of HCV in vitro is predictive of in vivo control of HCV during IFN-a/RBV/bocepravir therapy for HCV in the setting of HCV and HCV/HIV infection. The overall goal of these studies is to identify novel targets of focus for future therapeutic design in difficult to treat populations of HCV infected individuals, and to achieve a broader understanding of mechanisms underlying host control of chronic viral infection.