Hepatitis C virus (HCV) presents a significant public health problem with nearly 200 million infected people worldwide. Over the past three years, we have developed partnerships with clinicians and epidemiologists so that we can achieve better insight into immune pathogenesis of both acute and chronic HCV infection. My newly created research unit is committed to defining the complex interplay between virus and host from the perspective of type I interferons (IFNs) and IFN induced gene products. Furthermore, we aim to identify biomarkers predictive of viral clearance that could help identify, pre-treatment, which individuals will respond to their IFNα / ribavirin therapy. Specifically, we aim to: I. To define the role of IFN and IFN-induced genes in HCV clearance. This aim will utilize patient samples to define the role of endogenously produced IFNs in the clearance of HCV during acute infection and the paradoxical role they play in making chronically infected patients resistant to their exogenous IFN therapy. II. To characterize the effect of IFN and INF-induced gene products in the cross-priming of CD8+ T cells. This aim is based on our evidence that HCV-reactive CD8+ T cells are activated by an indirect pathway called cross-presentation and our recent data, which illustrates the complex ways in which type I IFNs can regulate this antigen presentation pathway. III. To determine the in vivo pro- and counter-inflammatory effect of IFN and INF-induced gene products in the cross-priming of CD8+ T cells. This aspect of the project will utilize mouse models to test our hypotheses regarding HCV disease pathogenesis. Our work and the studies outlined in this proposal will help push forward our understanding of the HCV disease pathogenesis and lead to the development of new diagnostic tools as well as strategies for improving upon existing therapeutic strategies.