Permeability of the blood-brain barrier to HIV-1 Tat

Infection with human immunodeficiency virus-1 (HIV-1) is associated with dysfunctions of the central nervous system (CNS). HIV-1 induces its effects on the CNS by a variety of mechanisms, including by shedding the neurotoxic viral proteins such as gp120 and Tat. Both HIV-1 and gp120 have been shown to cross the blood-brain barrier (BBB). It is has not been determined, however, whether blood-borne Tat can cross the BBB. Here, we found that Tat crosses the BBB by a nonsaturable mechanism with a unidirectional influx rate of about 0.490 microl/g/min. About 0.126% of an intravenous dose of Tat enters each g of brain. Radioactively labeled albumin injected simultaneously did not cross the BBB. The hypothalamus, occipital cortex, and hippocampus were the regions of the brain most permeable to Tat. Nonsaturable brain-to-blood efflux also occurred, most likely with reabsorption into the blood of the cerebrospinal fluid. In conclusion, we found that Tat crossed the BBB bidirectionally. Such permeability could provide a mechanism by which Tat produced on one side of the BBB could affect neural or immune function on the other side.