HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes

AIDS dementia is characterized by neuronal loss in association with synapti c damage. A central predictor for clinical onset of these symptoms is the i nfiltration of monocytes and macrophages into CNS parenchyma, Chronic HIV-1 infection of monocytes also allows these cells to serve as reservoirs for persistent viral infection. Using a coculture of endothelial cells and astr ocytes that models several aspects of the human blood-brain barrier, we exa mined the mechanism whereby the HIV-derived factor Tat may facilitate monoc yte transmigration. We demonstrate that treatment of cocultures on the astr ocyte side with HIV-1 Tat induced significant monocyte chemoattractant prot ein (MCP)-1 protein. Astrocytes, but not endothelial cells, were the source of this MCP-1 expression. Supernatants from Tat-treated cocultures induced significant monocyte transmigration, which was detected by 2.5 h after the addition of PBMC, Pretreatment of the supernatants from Tat-stimulated coc ultures with an Ab to MCP-1 completely blocked monocyte transmigration. Flo w cytometric analysis of Tat-stimulated PBMC demonstrated that Tat upregula ted expression of the chemokine receptor, CCR5, on monocytes in a time-depe ndent manner. Taken together, our data indicate that HIV-1 Tat may facilita te the recruitment of monocytes into the CNS by inducing MCP-1 expression i n astrocytes. These recruited monocytes may contribute to the pathogenesis of HIV-l-associated AIDS encephalitis and dementia.