Thrombotic microangiopathy is probably the most common form of microvascular injury in patients infected with human immunodeficiency virus (HIV). Virtually nothing is known about the pathogenesis of this disorder, although it is likely endothelial cell injury, perhaps occurring as a direct result of viral infection, is a critical early event. The goal of the proposed studies is to utilize a relevant animal model for this thrombotic microangiopathy to delineate the role of chemokine receptor expression and viral infection of parenchymal tissues in the pathogenesis of this disease process. Preliminary studies have shown that a proportion of macaques, when experimentally infected with HIV2, will develop thrombotic microangiopathy that is morphologically similar, if not identical, to human HIV-associated thrombotic microangiopathy. We will define the chronology of this disease process in infected macaques by means of clinical monitoring of serum and urine for evidence of organ dysfunction, immunological abnormalities including those involving lymphocyte subsets, and serologic evidence of infection. Morphologic correlation will be established by periodic biopsy and by necropsy studies of relevant affected organs including heart, lung, brain, and gut. Specialized studies of the tissues obtained will include immunohistochemical and in situ hybridization probes for the presence of virus and/or viral proteins, and synthesis of expression of multiple chemokine receptors within these organs and, most specifically, at sites of microvascular injury. The HIV-2 infected primate model provides a unique opportunity to study the pathogenesis of this microvascular disease process. In one specific aim, in vitro studies using cultured aortic and microvascular endothelial cells are proposed to further dissect the central mediators of endothelial injury that lead to a pro- thrombotic state. Finally, we propose to utilize the insights gained from these studies of non-human primate and in vitro systems to studies of relevant human biopsy tissue, in order to assess the relevance of chemokine receptor expression and viral infectivity on the development of microvascular injury in humans infected with HIV. These studies, in aggregate, will substantially enhance our understanding of the role of parenchymal expression of chemokine receptors in the pathogenesis of HIV-associated thrombotic microangiopathy, and offer possible strategies for therapeutic interventions that may ameliorate this disease process.