Journal
BRAIN RESEARCH
Volume 1436, Issue -, Pages 13-19Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2011.11.052
Keywords
HIV-1 Tat; Blood-brain barrier; Tight junction; MMP-9; Occludin
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Funding
- National Natural Science Fund [81000597, 81070248]
- Critical Project Foundation on Social Development of ShaanXi province [2010 K16-04-05]
- Natural Science Fund of ShaanXi province [2009JM4023]
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Brain homeostasis is maintained by the blood-brain barrier (BBB), which prevents the entrance of circulating molecules and immune cells into the central nervous system. The BBB is formed by specialized brain endothelial cells that are connected by tight junctions (TJ). Previous studies have proven that the Tat protein of human immunodeficiency virus type 1 (HIV-1) alters TJ protein expression. However, the mechanisms by which the alterations occur have not been characterized in detail. In this study, primary human brain microvascular endothelial cells (HBMEC) were exposed to recombinant HIV-1 Tat protein, and the effects on occludin were observed. Tat treatment decreased occludin mRNA and protein levels. This effect was partially abrogated by addition of the RhoA inhibitor C3 exoenzyme and the p160-Rho-associated coiled kinase (ROCK) inhibitor Y-27632. Meanwhile, Tat also induced MMP-9 expression. RNA interference targeting MMP-9 reduced both the paracellular permeability of Tat-treated HBMEC and the concentration of soluble occludin in supernatants from the cells. Taken together, these results show that the HIV-1 Tat protein disrupts BBB integrity, at least in part by decreasing the production of occludin. (C) 2011 Elsevier B.V. All rights reserved.
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