HIV-1 gp120 Effects in an in vivo Mouse Model for Endothelium Activation.

Morehouse School Of Medicine, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Clinical indications of disturbed vascular function during an HIV-1 infection are becoming increasingly clear. Studies have shown that during the progression to AIDS, factors are induced which are consistent with endothelium activation. Further, at least one study has shown that endothelium from a group of individuals infected with HIV-1 was disturbed, and the degree of leukocyte adherence increased significantly. Using HUVECs as a model, we have shown that soluble gp120/ lllb protein indeed induced apoptosis, and appear to do this through the CXCR4 chemokine receptor, and to a lesser extent through CCR5 chemokine receptor. We also have shown that soluble gp120/ lllb -induced apoptosis involves protein kinase-C (PKC), and the phorbol ester stimulated CXCR4 endocytosis pathway. Finally, we have evidence showing that gp120 appears to be inducing gene expression in these cells, significantly increasing levels of at least two endothelium expressed factors (vWF, and CD62E). Taken together, the above results suggest that, at least in vitro, gp120 has effects on endothelium compatible with both endothelium killing as well as endothelium activation. In this project, we will focus our attention on establishing a link between gp120 and endothelium activation in an in vivo mouse model for vascular activation. (A) In AIM-I and AIM-Il we will examine acute exposure to HIV-1 gp120 protein by doing one infusion of gp120 and then looking at endothelial activation and thrombus formation. (B) In AIM-Ill we will examine chronic exposure to the protein by doing multiple infusion of the protein over a period of time, and then examining endothelial activation formation. Finally, in AIM IV we will screen both serum from treated animals in AIM I-Ill (in vivo model), and HUVEC cultures (in vitro model) for changes in regulation or expression of factors involved in EC activation.