HIV TAT EFFECT ON ENDOTHELIAL CELL FUNCTION

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Infection of patients with Human Immunodeficiency Virus 1 (HIV) is associated with diverse alterations in endothelial function. These include syndromes marked by inappropriate endothelial cell (EC hyperplasia (primary pulmonary hypertension), incomplete differentiation (Kaposi's sarcoma), and acute inflammation (pneumonitis, myocarditis, encephalitis, pericarditis). Although these perturbations in EC function can be diffuse, direct infection of EC by HIV is unusual, may be restricted to certain vascular beds, and is generally abortive. Such endothelial alterations are therefore more likely to be the result of HIV-related circulating mediators, rather than of direct endothelial infection by retrovirus. We hypothesize that the secreted HIV transcription factor Tat acts to modify EC proliferation, differentiation, apoptosis, and expression of inflammatory molecules, and additionally, that these effects are modulated by the cytokines TNF alpha, IL-1 beta, and IFN gamma. We further hypothesize that the diverse and sometimes opposing effects of Tat are mediated by the oxidant-dependent differential activation of the various MAP Kinase signaling cassettes. Our preliminary data confirm that exposure of human EC to Tat acutely increases intracellular oxidant levels concomitant with activation of c-Jun amino terminal kinase (JNK). Further, Tat alters the TNF-alpha- mediated activation of JNK and the DNA-binding affinity of the transcription factor AP-1, a potential target of JNK. Our general objectives are to correlate oxidase assembly, oxidant production, MAPK activation, and DNA binding and promoter activation of transcription factors, with cell phenotype (proliferation, differentiation, apoptosis, inflammatory molecule expression, and leukocyte adhesion) in human EC exposed to Tat and cytokines, using a variety of interventions designed to dissect different signaling pathways. The significance of this work is to provide further insight into the cause of various AIDS-related vascular syndromes, as well as to understand the basis for fundamental EC functions in normal individuals. This may lead to specific treatments for HIV-infected patients, and may also suggest novel strategies for treatment of non-HIV related diseases through modulation of endothelial cell function.