title: HIV-1 Tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9.
abstract: 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.
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Ruifen
authors.initials: R
authors.lastname: Xu
authors.forename: Xuyang
authors.initials: X
authors.lastname: Feng
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Daocheng
authors.initials: D
authors.lastname: Wu
authors.forename: Lixian
authors.initials: L
authors.lastname: Xu
mesh_terms: D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D062793:Occludin; D034741:RNA, Small Interfering / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D034741:RNA, Small Interfering; D054322:tat Gene Products, Human Immunodeficiency Virus; C066737:RHOA protein, human; D020780:Matrix Metalloproteinase 9; D020742:rhoA GTP-Binding Protein