Cocaine opens the blood-brain barrier to HIV-1 invasion

Cocaine abuse has been associated with vasculitis and stroke, and is suspec ted to influence the progression of AIDS dementia. Cocaine may enhance HIV- 1 neuroinvasion by actions directed at the blood-brain barrier. HIV-1 appea rs to penetrate the human brain microvascular endothelial cell barrier by a paracellular route breached by tumor necrosis factor-alpha (TNF-alpha). Co caine's effects on the blood-brain barrier were investigated using human br ain microvascular endothelial cells and peripheral blood monocytes. Cocaine (10(-5) M and 10(-6) M) increased molecular permeability of the barrier an d viral invasion by the macrophage-tropic HIV-1(JR-FL) into the brain chamb er. Cocaine also augmented apoptosis of brain endothelial cells and monocyt es, increased secretion of four chemokines (interleukin-8, interferon-induc ible protein-10, macrophage inflammatory protein-1 alpha, and monocyte chem oattractant protein-1) and the cytokine, TNF-alpha, by human monocytes. TNF -alpha enhanced invasion of the brain compartment by macrophage-tropic, lym photropic, and bitropic HIV-1 strains. These data indicate that HIV-1 neuro invasion can be increased by (a) cocaine's direct effects on brain microvas cular endothelial cells and (b) paracrine effects of cocaine-induced pro-in flammatory cytokines and chemokines on the blood-brain barrier.