HIV-1 crosses the blood-brain barrier (BBB) early in the course of systemic infection and resides in brain macrophages and microglia. The integrity of the brain endothelium is regulated by intercellular tight junctions, which also play a critical role in HIV-1-entry into the brain. Disruption of tight junctions, including changes in claudin-5 expression, is common in HIV-1-infected patients. Recent evidence indicates that both exposure to HIV-1 and HIV-1 specific proteins, such as Tat protein, can contribute to alterations of expression and distribution of claudin-5 in brain endothelial cells and brain microvessels.