András Ibolya E, Pu Hong, Deli Mária A, Nath Avindra, Hennig Bernhard, Toborek Michal
Department of Surgery, University of Kentucky, Lexington, Kentucky, USA.
J Neurosci Res. 2003 Oct 15;74(2):255-65. doi: 10.1002/jnr.10762.
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.
血脑屏障（BBB）的破坏被广泛认为是人类免疫缺陷病毒（HIV）进入中枢神经系统（CNS）的主要途径。尽管这一过程的机制尚未完全明确，但紧密连接蛋白表达的改变至少在一定程度上促成了这一现象。紧密连接是脑微血管内皮细胞和血脑屏障的关键结构和功能元件。本研究的目的是检测HIV-1 Tat蛋白对紧密连接蛋白表达的影响。这些实验采用了脑微血管内皮细胞（BMEC）的原代培养物。BMEC暴露于Tat(1-72) 24小时导致claudin-1、claudin-5和闭锁小带（ZO）-2表达下降，而occludin和ZO-1的总水平保持不变。此外，BMEC短期（3小时）暴露于Tat(1-72)诱导了claudin-5免疫反应性的细胞重新分布。在将Tat(1-72)注射到小鼠右海马体的体内实验中也证实了Tat(1-72)诱导的claudin-5表达改变。这些发现表明，HIV-1 Tat蛋白可显著影响脑内皮细胞中特定紧密连接蛋白的表达和分布。仅特定紧密连接蛋白的改变表明Tat(1-72)对血脑屏障有精细调节作用。由于紧密连接蛋白对血脑屏障的屏障功能至关重要，这种改变可导致血脑屏障完整性的破坏，并有助于HIV进入大脑。
