Although HIV infection is generally associated with prolonged clinical latency, an expanding body of evidence points to the importance of early events for determining the outcome of HIV infection. Primary infection of humans with HIV-1 is often associated with an acute mononucleosis-like clinical syndrome characterized by fever, malaise, pharyngitis, lymphadenopathy, headache, diarrhea, rash and meningoencephalitis and is accompanied by a burst in virus replication detectable in the blood approximately 1-3 weeks following exposure. The appearance of specific antiviral immune responses is associated with dramatic reductions in the level of viremia, but there is no clearance of the virus. Limitations inherent in studying human subjects have precluded detailed investigation of many of the early events critical for virus transmission, dissemination and eventual disease progression. The SIV/macaque model will be used to address these critical issues. Whether there is selective transmission of particular SIV genotypes across the mucosal surface will be determined. The initial cellular targets of primary infection by the mucosal and intravenous routes will be identified and the sequential targets of the spreading viral infection will be- characterized. Analyses will include subsets of CD4+ lymphocytes and progenitor cells in thymus and bone marrow as possible preferential targets. The influence of varying viral genotype on transmission, dissemination to tissues and tissue-specific disease manifestations will be investigated. Finally, the importance of cytotoxic T lymphocytes for controlling the early burst in virus replication will be investigated in this manipulable experimental setting. These studies will be achieved through the cooperation of three principal investigators at the New England Regional Primate Research Center with extensive experience in the disciplines of Virology, Molecular Biology, Pathology and Immunology.
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