The objective of the proposal is to test the hypothesis that the determinants of sexual/mucosal transmission of primate lentiviruses are viral replication at the portal of entry and the local virus-specific cellular immune response. If the host mounts an effective immune response before there is sufficient replication to generate ineradicable latently infected cells or cytotoxic T lymphocyte (CTL) escape mutants, infection will be aborted or transient. If not, infection will be persistent and progress to immune depletion and disease. Identifying the critical determinants of outcome will lay the foundations for design and evaluation of lentiviral vaccines. Experiments to identify these determinants and test their hypothesized role in sexual transmission are proposed that utilize a non-human primate model, rhesus monkeys infected intravaginal with simian immunodeficiency virus (SW) or SIV-HIV chimeras (SHIV) with different replicative capabilities. The extent of viral replication will be assessed locally, in the draining lymph nodes, and systemically, by doublelabel in situ PCR and hybridization methods that identify the number and types of infected cells in tissue specimens and the state of viral gene expression (latent or productive infection) by the abundance and class of viral transcripts. The timing and breadth of the virus-specific cellular immune response in specific anatomic compartments and evidence of CTL escape mutants will be sought by characterizing specific CTL epitopes with defined MHC class I contexts, the clonality of the CD8+ T lymphocyte response, and changes in the sequences of the epitopes in the evolving viral quasi-species. These analyses will provide insight into the immune correlates of protection at the portal of entry in sexual transmission of lentiviruses.
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