The major goal of this Project is to establish an animal model for human AIDS in which to study viral determinants of immunodeficiency and immunologic correlates of resistance to infection or disease. Simian immunodeficiency virus (SIV) isolated from sooty mangabey monkeys (SIVsm) readily induces an immunodeficiency syndrome in macaques similar to human AIDS, therefore this strain has been the focus of pathogenesis and vaccine studies. The genetic analysis of African strains has focused on SIVsyk recovered from a sykes monkey and SIV isolated from the tantalus sub-species of African green monkey (AGM). Sequence analysis of the sykes isolate indicated that it is a distinct new member of the primate lentiviruses. The tantalus strain groups with other African green monkey SIVs but forms its own species-specific subgroup. Pathogenesis studies have addressed: (i) the molecular pathology of end-stage SIVsm-induced immunodeficiency; and (ii) the extent and rate of genetic drift of SIVsm molecular clones. High levels of unintegrated viral DNA were observed in most tissues. Virus existed as a swarm of related genomes and resided mainly within macrophages. Ten distinctive (in terms of sequence and tropism) infectious clones were obtained directly from the spleen of one of these macaques. Progeny virions of one of these clones induced a persistent decline in circulating CD4 lymphocytes within 6 months of infection. Analysis of genetic drift of SIVsm molecular clones demonstrated that SIV undergoes significant variation upon replication in vivo; the variation is far greater in the envelope gene than within the integrase gene. Finally, full-length infectious molecular clones of SIVstm from stumptail macaques and SIVsmi/PBj, the acutely lethal variant, were generated. The SIVstm clone groups with other reported SIVmac clones but is genetically distinct. Virus stocks generated from two PBj clones (sharing a common 3' end) induced the typical PBj syndrome of acute early death. Finally, an inactivated whole SIV vaccine was tested in macaques. Vaccinated monkeys developed a strong SIV antibody response and were protected from challenge with cell-free virus of an heterologous SIV strain as well as the homologous SIV strain used to produce the vaccine. The vaccinated animals will be challenged with cell-associated virus in the near future.