HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells.
Disruption of the blood-brain barrier (BBB) is widely believed to be the main route of human immunodeficiency virus (HIV) entry into the central nervous system (CNS). Although mechanisms of this process are not fully understood, alterations of tight junction protein expression can contribute, at least in part, to this phenomenon. Tight junctions are critical structural and functional elements of cerebral microvascular endothelial cells and the BBB. The aim of the present study was to examine the effects of HIV-1 Tat protein on expression of tight junction proteins. Primary cultures of brain microvascular endothelial cells (BMEC) were employed in these experiments. A 24-hr exposure of BMEC to Tat(1-72) resulted in a decrease of claudin-1, claudin-5, and zonula occludens (ZO)-2 expression, whereas total levels of occludin and ZO-1 remained unchanged. In addition, a short (3-hr) exposure of BMEC to Tat(1-72) induced cellular redistribution of claudin-5 immunoreactivity. Tat(1-72)-induced alterations of claudin-5 expression also were confirmed in vivo where Tat(1-72) was injected into the right hippocampus of mice. These findings indicate that HIV-1 Tat protein can markedly affect expression and distribution of specific tight junction proteins in brain endothelium. Alterations of only distinct tight junction proteins suggest a finely tuned effect of Tat(1-72) on the BBB. Because tight junction proteins are critical for the barrier function of the BBB, such alterations can lead to disturbances of the BBB integrity and contribute to HIV trafficking into the brain.
D015526:AIDS Dementia Complex / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology; D062445:Claudin-1; D062507:Claudin-5; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D015696:Gene Products, tat / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology; D062827:Zonula Occludens-2 Protein; D054322:tat Gene Products, Human Immunodeficiency Virus
C568108:CLDN1 protein, human; D062445:Claudin-1; D062507:Claudin-5; C568113:Cldn1 protein, mouse; C568114:Cldn1 protein, rat; C491511:Cldn5 protein, mouse; C491510:Cldn5 protein, rat; D015696:Gene Products, tat; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; D010446:Peptide Fragments; C569046:TJP2 protein, human; C569047:Tjp2 protein, mouse; D062827:Zonula Occludens-2 Protein; D054322:tat Gene Products, Human Immunodeficiency Virus