PNEUMOCYSTIS CARINII PNEUMONIA MODEL IN RHESUS MACAQUES

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Pneumocystis carinii pneumonia is a primary cause of morbidity and mortality in immunocompromised patients, with particularly high infection rates in patients with acquired immunodeficiency syndrome (AIDS). Studies of the pathophysiology of Pneumocystis carinii pneumonia (PCP), host immune responses, and molecular characterizations of the organism have relied on animal models because of the lack of continuous in vitro culture systems. Although these animal models have been useful in producing information regarding the nature of the organism and the complex host-parasite interaction, the relevance to human PCP has been questioned since they generally involve broadly immunosuppressed animals. In addition, much evidence has been accumulated that demonstrates host species specific phenotypic and genotypic variation. For these reasons, the development of a reproducible, nonhuman primate model of PCP which mimics the disease seen in AIDS would provide several advantages for studying the pathogenesis of PCP and the molecular aspects of host species variations in a model most closely related to humans. Simian immunodeficiency virus (SIV) infected rhesus macaques develop spontaneous PCP, and preliminary evidence suggests that this occurs when peripheral CD4+ T cells counts falls below approximately 30 percent of the total T cells. The occurrence of PCP in SIV infected animals is not predictable due to individual host variability, environmental factors, and the variability in the course of the SIV infection. The primary goals of this study are to develop a reproducible PCP infection in immunocompromised, SIV infected rhesus macaques and to use this model to characterized the phenotypic and genotypic variation of simian derived P. carinii. It is our hypothesis that this model will most closely resemble PCP in AIDS and that the simian P. carinii will be most closely related to human P. carinii at the molecular level. To test these hypotheses, we propose to develop a PCP model by initiating a P. carinii infection in SIV infected rhesus macaques. The P. carinii infection will be initiated in monkeys when the SIV -induced decline in peripheral CD4+ T cells reaches 30 percent of the total peripheral blood T cells. Various manifestations of the disease progression will be monitored and simian P. carinii will be recovered for molecular and antigenic characterizations. These studies will address the question of similarities between simian and human P. carinii and determine the relevance of the nonhuman primate model, thus providing the means to study many aspects of PCP previously unapproachable due to the limitations of other animal models.