Caccuri, FrancescaNeves, VeraGano, LurdesCorreia, João D. G.Oliveira, Maria-CristinaMazzuca, PietroCaruso, ArnaldoCastanho, Miguel A. R. B.2023-05-232023-05-232022Journal of Virology, January 2022, Volume 96, Issue 1 e01200-210022-538Xhttp://hdl.handle.net/10451/57519© 2022 American Society for Microbiology. All Rights Reserved.Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation in HIV-1-infected (HIV) patients. Furthermore, detection of the HIV-1 matrix protein p17 (p17) in the central nervous system (CNS) and its ability to form toxic assemblies in the brain have 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 rapid brain uptake with 0.35%  0.19% of injected activity per gram of tissue (IA/g) 2 min after administration, followed by brain accumulation with 0.28%  0.09% IA/g after 1 h. The interaction of p17 with 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.engHIV-1 matrix protein p17HIV-associated neurocognitive disorderBloodbrain barrierTranscytosisin vivo biodistributionjournal article10.1128/JVI.01200-211098-5514