The hepatitis C virus (HCV) infects about 2 percent of humans globally. Although the infection resolves spontaneously in some individuals, it usually causes a persistent life-long infection that is associated with progressive liver disease, including hepatitis cirrhosis, and hepatocellular carcinoma. The outcome of infection is determined in the first few weeks after infection but the host virus relationship during this period is poorly characterized. We postulate that HCV replicates in most hepatocytes immediately after infection and is eventually controlled by cellular immune responses control partial control of virus replication that slows progression of disease. T lymphocytes expressing CD4 or CD8 cell surface markers merit special consideration in this model. They recognize viral antigens presented on the surface of infected cells by MHC class II and I molecules, respectively. Both subsets produce cytokines with the potential to inhibit HCV replication and CD8+ T cells can terminate the virus replication cycle by killing infected targets. This is Project 1 of a 3 project U19 proposal to define the role of immunity in hepatitis C. In this project we propose to characterize the frequency and kinetic of HCV-specific T cell responses in chimpanzees, the only animal model of human HCV infection. These data will be integrated with a molecular analysis of T cell responses (Project 2) and virus replication and evolution (Project 3) to establish a temporal kinetic relationship between host immune responses and control of acute phase virus replication. In addition, animals will be temporarily depleted of CD4+ and CD8+ 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. Three fundamental questions will be addressed: 1. Does acute phase HCV replication subside when HCV-specific T lymphocytes infiltrate the liver? 2. Does depletion of CD4+ or CD8+ T cells immediately before infection prolong the acute phase of virus replication or delay the onset of hepatitis? 3. How does deletion of CD8+ T lymphocytes alter virus replication in the chronic phase of infection?
Showing the most recent 10 out of 19 publications
