Hepatitis C virus (HCV) infects about 2 percent of the world's population. Approximately 70 percent of these individuals develop persistent, life-long viremia and are at increased risk for serious liver disease and even hepatocellular carcinoma. How HCV avoids elimination by host immune responses is not understood. Our hypothesis is that effective control of HCV replication requires class I MHC-restricted cytotoxic T lymphocytes (CTL) that target several viral proteins simultaneously, and that this multi-specific response is lacking in the liver of persistently infected individuals. The common chimpanzee (Pan troglodytes) is the only animal model for studying mechanisms of protective immunity against HCV. We have identified nine chimpanzees of defined class I MHC haplotype that had been challenged with HCV-1, a genotype 1a virus that is molecularly cloned and sequenced. Six are chronically infected and three resolved plasma viremia within a few weeks of experimental challenge. The three specific aims seek to: 1. Define the frequency and repertoire of intrahepatic HCV-specific CD8+ T cells in 6 chronically infected chimpanzees and examine their relationship to plasma virus load. A related goal is to determine the fate of virus-specific CTL that were present in the liver of these animals during the acute phase of infection. 2. Determine if the liver is an important site of CD8+ and CD4+ T cell memory in individuals with resolved HCV infections, and compare their frequency and repertoire with those in chronically infected animals. 3. Re-challenge chimpanzees with resolved HCV-1 infections to establish a temporal relationship between control of virus replication and activation or expansion of memory HCV-specific T cells in the liver. Results from these studies should confirm our preliminary observation that the liver is an important (and perhaps the dominant) site of T cell memory in individuals recovering from acute hepatitis C, and that these responses can perhaps provide life-long protection from chronic HCV infection. Moreover, comparison of CTL repertoire, frequency, and longevity in individuals with resolved and chronic infections could identify defects in cell-mediated immune responses that contribute to persistence of the virus.
