The human immunodeficiency viruses, HIV-1 and HIV-2, are members of an extensive but poorly characterized family of primate lentiviruses that appear to have their origins in African primates. Each of the human viruses presumably arose relatively recently following cross-species transmission from a naturally- infected primate to humans. In the case of HIV-2, the precursor appears to be SIVsm from sooty mangabey monkeys (Cercebus atys) whereas the origins of HIV-1 are less clear. The goals of this project are twofold. The first is to molecularly characterize novel SIV isolates from wild-caught African monkeys more extensively with a particular emphasis on those isolated from members of the Cercopithecus genus. The underlying hypothesis of these studies is that the primate lentiviruses originated and coevolved within monkeys of the Cercopithecus genus and that examples of SIV strains in other monkeys are evidence of more recent cross-species transmission. We initiated these studies by characterizing SIV isolates from three of the species of African green monkeys (vervets, grivets and tantalus), then SIV from Sykes monkeys (C. albogularis) and most recently SIV from l?hoest monkeys (C. l?hoesti). These studies demonstrated that SIVlhoest is a new member of the SIVmnd lineage, named for mandrill (Mandrillus sphinx), the source of the original isolate. The geographic distance in the habitats of l?hoest monkeys and mandrills rule out the possibility of that either virus resulted from cross-species transmission between mandrills and l?hoest monkeys. The distant phylogenetic relationship between these monkeys also is inconsistent with co-evolution in their respective host species. Thus we propose that the most likely explanation is that SIVmnd is the result of cross-species transmission of SIV from a West African relative of the l?hoest monkey, either suntailed (C. solatus) or preussis (C. presussi) monkeys. To evaluate this hypothesis we are presently characterizing SIV isolated from a suntailed monkey. A secondary but equally important goal of this project is to study the mechanisms underlying the apparent lack of pathogenicity of these SIV isolates for their natural host species with emphasis on SIVagm from vervet monkeys. Both SIVsm from sooty mangabeys and SIVagm from African green monkeys are capable of inducing AIDS in macaques but are not virulent for their natural host. We also evaluated the pathogenicity of SIVlhoest in macaques and observed robust primary viremia, lymphadenopathy and declining CD4 lymphocyte counts consistent with progression to AIDS. Therefore, SIVlhoest also appears to be capable of inducing AIDS in macaques. To more extensively study the underlying mechanisms for differential virulence of SIV, we derived the molecularly cloned, pathogenic SIVagm9063-2 that induces AIDS in pigtailed macaques and Asian species but results in asymptomatic infection of African green monkeys and have developed quantitative assays for measuring viral RNA in plasma samples. We will extend these studies to evaluating sequential viral load in the two species as well as attempting to perturb the viral-host balance in the natural host by immune activation, chemical immune suppression, or effective antiviral therapy.