HIV and SIV induce a slow progressive disease, characterized by the massive loss of memory CD4+ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. Approximately 20 to 25% of rhesus monkeys infected with the SIVsm543 strain rapidly progress to disease within the first six months of infection. Such rapid progressors (RP) experience persistently high levels of plasma viremia/p27 antigenemia, undetectable or transient anti-SIV antibody responses that wane within three to four weeks of virus inoculation, and the early onset of clinical disease characterized by marked weight loss, chronic diarrhea, and cachexia. We have assessed CD4+ T cell dynamics and disease progression in 12 SIV infected rhesus monkeys for nearly two years. Three macaques exhibiting a rapid progressor (RP) phenotype experienced rapid and irreversible loss of memory, but not naive, CD4+ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within four to six months of virus inoculation. In contrast, SIV infected conventional progressor (CP) animals sustained marked but incomplete depletions of memory CD4+ T cells and continuous activation/proliferation of this T lymphocyte subset. This was associated with a profound loss of naive CD4+ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4+T cells, which are being eliminated by direct virus killing and activation induced cell death, requires the continuous differentiation of naive into memory CD4+ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naive CD4+T cell pool and the development of disease.[unreadable] [unreadable] In a second study, the pathologic lesions and distribution of virus and target cells in SIV infected RPs and CP animals were evaluated at the time of death. RP macaques developed a wasting syndrome characterized by severe SIV enteropathy in the absence of opportunistic infections. In contrast, opportunistic infections were frequently observed in CP macaques. In situ hybridization studies demonstrated higher levels of virus expression in lymphoid tissues (p <0.001) of RP macaques, and a broader distribution to include many non-lymphoid tissues. Finally, SIV was preferentially expressed in macrophages in RP macaques; whereas, the primary target cell in CP macaques was T lymphocytes at endstage disease. These data suggest distinct pathogenic mechanisms leading to the death of these two groups of animals, with CP macaques being more representative of HIV induced AIDS in humans.