TAT-HUMAN IMMUNODEFICIENCY VIRUS-1 INDUCES HUMAN MONOCYTE CHEMOTAXIS BY ACTIVATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR RECEPTOR-1

Human immunodeficiency virus-1 (HIV-1) Tat protein can be released by infected cells and activates mesenchymal cells. Among these, monocytes respond to Tat by migrating into tissues and releasing inflammatory m ediators, In the present study, we have examined the molecular mechani sm of monocyte activation by Tat, showing that this viral protein sign als inside the cells through the tyrosine kinase receptor for vascular endothelial growth factor encoded by fms-like tyrosine kinase gene (V EGFR-1/Flt-1). Subnanomolar concentrations of Tat induced monocyte che motaxis, which was inhibited by cell preincubation with vascular-endot helial growth factor-A (VEGF-A). This desensitisation was specific for VEGF-A, because it not was observed with FMLP. In addition, the solub le form of VEGFR-1 specifically inhibited polarization and migration i nduced by Tat and VEGF-A, thus confirming the common use of this recep tor. Binding studies performed at equilibrium by using radiolabeled Ta t showed that monocytes expressed a unique class of binding site, with a kd of approximately 0.2 nmol/L, The binding of radiolabeled Tat to monocyte surface and the cross-linking to a protein of 150 kD was inhi bited specifically by an excess of cold Tat or VEGF-A. Western blot an alysis with an antibody anti-VEGFR-1/Flt-1 performed on monocyte phosp hoproteins immunoprecipitated by an monoclonal antibody antiphosphotyr osine showed that Tat induced a rapid phosphorylation in tyrosine resi due of the 150-kD VEGFR-1/Flt-1. Taken together, these results suggest that biologic activities of HIV-1 Tat in human monocytes may, at leas t in part, be elicited by activation of VEGFR-1/Flt-1. (C) 1997 by The American Society of Hematology.