Nonhuman primate models are crucial to the design and evaluation of human immunodeficiency virus (HIV) vaccines. The definition of protective immune responses is one of the most important applications of these models. Mauritian Cynomolgus macaques are geographically isolated, descending from a small founder population of Indonesian macaques less than 500 years ago. We have identified multiple high-frequency major histcompatibility complex class I (MHC-I) alleles in these animals, as well as groups of animals that are MHC-I identical. We hypothesize that CD8+ T-lymphocyte responses against simian immunodeficiency virus (SIV) are predictable and reproducible in animals with the same MHC-I genetics, and that these responses are the primary determinant of viral 'setpoint' during chronic infection. Here we propose a series of experiments designed to test this hypothesis and lay the foundation for using Mauritian Cynomolgus macaques in other studies of SIV-specific cellular immunity. ? ? In Specific Aim 1: We will define CD8+ T-lymphocyte epitopes recognized in two groups of MHC-I identical Mauritian Cynomolgus macaques infected with SIVmac239. We will screen peptide pools for CD8+ T-lymphocyte reactivity, mapping the responses mounted by each group of animals. These epitopes will be the first ones described in this population of macaques. ? ? In Specific Aim 2: We will measure SIV suppression by CD8+ T-lymphocytes from two groups of MHC- I identical animals. In vivo suppression will be assessed by tracking plasma virus concentrations throughout SIV infection. We will also determine how effectively CD8+ T-lymphocytes from these animals suppress viral replication in purified CD4+ T-lymphocytes in vitro. ? ? We expect that each group of MHC-I identical animals will mount stereotypic CD8+ T-lymphocyte responses that determine the level of plasma viremia during chronic infection, the best predictor of HIV/SIV disease progression. Moreover, this research will establish the foundation for using Mauritian Cynomolgus macaques in other vaccine and pathogenesis studies. These studies exploit the unique genetics of Mauritian Cynomolgus macaques to explore fundamental questions about the protective value of CD8+ T-lymphocyte responses in SIV infection. ? ? ?
