MONOCYTE-DERIVED DENDRITIC CELLS AND MONOCYTES MIGRATE TO HIV-TAT RGDAND BASIC PEPTIDES

Objective and design: Extracellular Tat released from HIV-1-infected c ells is a mitogenic and motogenic factor for endothelial and Kaposi's sarcoma (KS)-derived cells and is angiogenic in vivo. Here we show for the first time that Tat induces migration of human dendritic cells in a concentration-dependent manner and that the Arg-Gly-Asp (RGD) and b asic Tat peptides contribute to dendritic and monocyte cell migration. In vivo, Tat stimulates invasion of macrophages into a matrigel spong e. Methods: Monocyte and dendritic cell chemotaxis was assessed using the Boyden chamber assay. Results: Tat induced migration of monocyte-d erived dendritic cells at the same levels as the N-formyl-Met-Leu-Phe peptide, and of monocytes at levels comparable to RANTES. Peptide mapp ing of the chemotactic activity of Tat showed that the RGD domain, whi ch has been shown to support integrin-mediated cell migration, and the basic domain which binds and activates the tyrosine kinase receptor K DR on endothelial cells, both had activity. Antibody-blocking experime nts indicate that responses to the RGD domain was inhibited by beta 1 and alpha v beta 3 integrin blocking antibodies. Combination of the Ta t RGD and basic peptides did not show additive effects; however, Tat c o-operated with macrophage-chemotactic protein or RANTES in inducing m onocyte migration. Conclusions: Our results show that Tat can act as a chemoattractant for dendritic cells, and that both the RGD and basic domains are involved in this response. These same domains attract mono cytes. The alpha v beta 3 and beta 1 integrins are equally involved in Tat-induced monocyte migration, while the alpha v beta 3 integrin lar gely mediates the dendritic cell response to Tat.