PATHOGENESIS OF HIV ASSOCIATED HUS/TTP IN CHILDREN

血栓性血小板减少性紫癜-溶血性尿毒症综合征（TTP-HUS）

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, central nervous system abnormalities, and renal dysfunction. This syndrome is dominated by neurological signs in adults and renal failure in children. Microvascular thrombosis is the typical lesion and endothelial injury is likely the initial event. Based on previous studies by other investigators and our own clinical and pathological data obtained from children with HIV- associated HUS/TTP, we hypothesized that the more severe prognosis of HUS/TTP in HIV-1 infected children is related tin part to HIV-1 enhancement of microvascular injury and cell behaviors associated with re- endothelialization of renal capillaries. Our preliminary data obtained from HIV-1 transgenic mice and children with HIV associated HUS/TTP, indicate that HIV-1 stimulates synthesis of extracellular matrix proteins, adhesion, growth and organization/differentiation of renal microvessels. These changes facilitate the thrombotic obstruction of capillaries, delaying the process of re-canalization and leading to chronic renal failure or death due to systemic microvascular involvement. Three specific aims are proposed. First, we will determine whether cultured human renal microvascular endothelial cells are infected and injured when exposed to cell free virions or to HIV-1 infected lymphocytes/macrophages derived from children with HIV associated HUS-TTP. Second, we will evaluate growth, adhesion, migration and morphological differentiation of renal microvascular endothelial cells in vitro, in the presence or absence of tat or the HIV-1 virus. The mechanisms by which tat -HIV-1 modulate these behaviors will be examined by characterizing activities that have been associated with re-canalization of the vascular lumen including, matrix protein synthesis, migration, differentiation, expression of integrin receptors, and production of extracellular matrix proteases. Third, based on these results, we will develop a transgenic mouse model of HIV associated HUS/TTP. We expect these experiments will define the response of the renal microvascular endothelium to the HIV-1 virus, provide useful data regarding the modulation of renal endothelial cell behaviors by HIV-1 during the process of re-canalization, and establish a clinically relevant animal model to test novel therapies against HIV-associated HUS/TTP in children.