The majority of persons acutely infected with hepatitis C virus (HCV) will develop chronic infection, but not all subjects go on to develop the complications of chronic infection such as hepatic fibrosis or steatosis. Current antiviral treatments are neither effective nor available for most persons with chronic HCV infection, and thus chronic infection remains a significant health problem. The natural history of HCV liver disease combined with the epidemiology of this infection has resulted in an increasing prevalence of persons with chronic HCV, and rising rates of hepatic decomposition and hepatocellular carcinoma. However, our understanding of the host and viral determinants of liver disease progression are poorly understood. This program project will address the determinants of liver injury in chronic HCV infection, using cohorts with rapid disease progression and controls to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. This will be accomplished in three integrated projects: The first Project will test the hypothesis that failure of the CD4 response results in an inappropriate CD8+ cytotoxic T lymphocyte (CTL) and natural killer T (NKT) response that serves to drive fibrosis and viral evolution. The second Project will characterize the role of oxidative stress in chronic HCV and the mechanisms of hepatic steatosis. The third Project will determine which viral and host factors drive hepatic stellate cell activation as a key step in fibrosis. The projects will be supported by a clinical core, which will maintain a repository of clinical samples derived from cohorts with rapid progression (transplant, HIV/HCV co-infection and Schistosoma mansoni co-infection) as well as more slowly progressive disease. This joint use of common clinical material will facilitate maximal integration of results. Through this unique cooperative approach, we will determine which viral and host factors contribute to fibrosis, the major complication of chronic HCV infection, which might suggest new therapeutic strategies to prevent liver disease progression.