The hepatitis C virus (HCV) is highly adapted in its human host and can cause progressive liver disease including hepatitis, cirrhosis, and hepatocellular carcinoma over a period of years or decades. The role of the host immune system in control of virus replication is poorly understood. Cellular immune responses mediated by T lymphocytes expressing the CD4 or CD8 surface antigens may play a role in spontaneous resolution of acute hepatitis C and in control of ongoing virus replication in those who develop persistent infections. The central theme of this U19 application is that HCV replicates in most hepatocytes immediately after injection but is eventually controlled by acute phase cellular immune responses. It is postulated that in those individuals developing persistent infections, the immune response limits but does not terminate virus replication, thus slowing disease progression. Three projects making up this U19 application will investigate the host-virus relationship in acute and chronic infection of chimpanzees, the only animal model for HCV infection. Specifically, we will define the kinetic of acute phase virus replication and animals will be temporarily depleted of CD4+ and CD 8+ T cells by administration of subset-specific antibodies to directly assess their role in acute phase virus replication and possibly as mediators of hepatocellular injury. Finally, this same approach will be used to examine whether CD8+ T cells provide partial control of virus replication in chronic hepatitis C.