Chronic hepatitis C is an important cause of severe liver disease in the United States and throughout the world. Hepatitis C virus (HCV) shows a strict range, with persistent infection observed only in humans and the experimental chimpanzee model. In the majority of humans and chimpanzees, infection with HCV results in persistent and chronic viremia despite an ongoing host immune response. In humans, severe hepatitis, liver cirrhosis, hepatocellular carcinoma and death are relatively common consequences of chronic hepatitis C over several decades. It is presently unknown whether the host immune response is protective in HCV infection., or in fact the host response is responsible for most of the disease manifestations. Preliminary studies in humans suggest the HCV mutations result from immune responses and lead to the formation of genetically diverse viral populations within the infected host. Such viral populations are termed quasispecies, and this dynamic feature of HCV infection is thought to contribute in a major way to viral persistence. This project is part of a proposed NIH Cooperative Center grant aimed at studying viral and host factors related to HCV clearance, HCV persistence, and activity of liver disease in the chimpanzee model. Detailed investigation of HCV infection and cellular immune responses will be conducted on 16 animals with HCV infection. Tissue collected at other centers will be forwarded to Seattle for virology studies. Virological analyses of HCV replication kinetics in liver tissue using in situ hybridization techniques, and HCV quasispecies evolution patterns in blood and tissue will be conducted at the University of Washington Viral Hepatitis Laboratory under the direction of Dr. Gretch. The work will provide important new information on the dynamic interactions between the host immune response and the persistently replicating HCV quasispecies populations.