Grant: Chair: GlaxoSmithKline Partnered

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the primary causes of chronic viral hepatitis that can lead to end-stage liver disease (cirrhosis) or hepatocellular carcinoma. There is an estimated 400 million chronic carriers of HBV and 170 to 200 million chronic carriers of HCV. Research on these viruses has been limited by the lack of adequate cell culture systems on animal models. We have recently developed an immune-compromised transgenic mouse (SCID/beige Alb-uPA) that can accept human hepatocytes transplanted via intrasplenic injection. These mice develop chimeric human/mouse livers and are proving very valuable for the study of the innate immune responses, the responses to biological and small molecule antiviral agents, and to study the host and viral genetics contributing to chronic viral infection as opposed to an acute infection that resolves quickly. While we initially thought this model was excellent for studying viral infection and replication, recent studies have shown the model can be expanded to study virally-induced oxidative stress and apoptosis and has provided key insights into the underlying pathogenesis of viral-induced fibrosis - a precursor to the development of cirrhosis. The proposal outlined in this study examines several genes that are involved in "putting the brakes" on the innate immune response to HCV infection. We will use the mouse model to examine the effect of inhibiting these "braking proteins" and essentially taking the "brakes" off the innate immune response may permit a stronger response to clear HCV infection.