The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha 5 beta 1 and alpha v beta 3integrins and by mobilizing sequestered basic fibroblast growth factor

The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been sho wn to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals . In this study, we investigated the molecular mechanisms responsible for t he angiogenic effects of Tat, The results shown herein indicate that two di fferent Tat domains cooperate to induce these effects by different pathways . The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyt erminal of Tat mediates vascular cell migration and invasion by binding to the alpha 5 beta 1 and alpha v beta 3 integrins, This interaction also prov ides endothelial cells with the adhesion signal they require to grow in res ponse to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects rese mble those of extracellular matrix proteins, suggesting that Tat enhances a ngiogenesis and promotes KS progression by a molecular mimicry of these mol ecules. (C) 1999 by The American Society of Hematology.