The HIV-1 matrix protein p17 does cross the Blood-Brain Barrier.

Abstract

Human immunodeficiency virus type-1(HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation in HIV-1-infected (HIV+) patients. Furthermore, the HIV-1 matrix protein p17 (p17) detection in the central nervous system (CNS) and its ability to form toxic assemblies in the brain has been recently confirmed. Here we show for the first time using both an in vitro blood-brain barrier (BBB) model and in vivo biodistribution studies in healthy mice that p17 can cross the BBB. There is fast brain uptake with 0.35 ± 0.19% of injected activity per gram of tissue (I.A./g) two minutes after administration, followed by brain accumulation with 0.28 ± 0.09% I.A./g after 1 h. The interaction of p17 with the chemokine receptor 2 (CXCR2) at the surface of brain endothelial cells triggers transcytosis. The present study supports the hypothesis of a direct role of free p17 in neuronal dysfunction in HAND by demonstrating its intrinsic ability to reach the CNS. IMPORTANCE The number of patients affected by HIV-1-associated neurocognitive disorder (HAND) ranges from 30 to 50% of HIV-infected (HIV+) patients. The mechanisms leading to HAND development need to be elucidated, but the role of secreted viral proteins, chemokines, and proinflammatory molecules appears to be clear. In particular, the blood-brain barrier (BBB) represents a route for entry into the central nervous system (CNS) thus playing an important role in HAND. Several findings suggest a key role for the HIV-1 matrix protein p17 (p17) as a microenvironmental factor capable of inducing neurocognitive disorders. Here we show, the ability of the p17 to cross the BBB and to reach the CNS thus playing a crucial role in neuronal dysfunction in HAND.