In this research article we describe how human immunodeficiency virus type 1 (HIV-1) transactivating protein (Tat) can induce profound and potentially lasting changes in the way neurons from the cerebral cortex are able to process proteins and buffer calcium, two functions that are critical to normal communication in the brain. We identify the ryanodine receptor protein as the mediator of these effects, and as proof of principle, we demonstrate that dantrolene, a drug used to block the ryanodine receptor, can block these toxic effects. Additionally, we demonstrate the lasting consequences of exposure to a single dose of Tat in a mouse model of HIV-1 infection of the brain. Finally, we show that similar changes occur in cerebral cortex in brain tissue of people with HIV-1 infection and neurologic disease. These findings help further our understanding of how HIV-1, despite suppression of its life cycle by highly active antiretroviral therapy (HAART), can still initiate progressive neurologic disease.
