Monocyte-derived dendritic cells and monocytes migrate to HIV-Tat RGD and basic peptides

Objective and design: Extracellular Tat released from HIV-1-infected cells 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 basic Tat peptides contribute to dendritic and monocyte cell migration. In vivo, Tat stimulates invasion of macrophages into a matrigel sponge. Methods: Monocyte and dendritic cell chemotaxis was assessed using the Boyden chamber assay. Results: Tat induced migration of monocyte-derived dendritic cells at the same levels as the N-formyl-Met-Leu-Phe peptide, and of monocytes at levels comparable to RANTES. Peptide mapping of the chemotactic activity of Tat showed that the RGD domain, which has been shown to support integrin-mediated cell migration, and the basic domain which binds and activates the tyrosine kinase receptor KDR on endothelial cells, both had activity. Antibody-blocking experiments indicate that responses to the RGD domain was inhibited by beta 1 and alpha v beta 3 integrin blocking antibodies. Combination of the Tat RGD and basic peptides did not show additive effects; however, Tat co-operated with macrophage-chemotactic protein or RANTES in inducing monocyte 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 monocytes. The alpha v beta 3 and beta 1 integrins are equally involved in Tat-induced monocyte migration, while the alpha v beta 3 integrin largely mediates the dendritic cell response to Tat.