HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier
HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier
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DOI：
10.1038/sj.jcbfm.9600254
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发表时间：
2006-08-01
影响因子：
6.3
通讯作者：
Toborek, Michal
中科院分区：
文献类型：
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作者：
Hayashi, Kentaro;Pu, Hong;Toborek, Michal
尽管高效抗逆转录病毒治疗（HAART）取得了显著进展，但人类免疫缺陷病毒（HIV）感染的中枢神经系统（CNS）并发症仍然是HIV/获得性免疫缺陷综合征的严重健康风险。用于HAART的特定药物是外排转运系统的底物，如多药耐药相关蛋白（MRP），其存在于脑微血管内皮细胞（BMEC）和星形胶质细胞上，即形成血脑屏障（BBB）的主要细胞类型。因此，HAART中使用的药物被主动地从CNS中去除，并且不能有效地抑制HIV在脑中的复制。为了研究这一过程的潜在机制，本研究的目的是解决这一假设，即HIV达特蛋白可以有助于在BBB水平的MRP表达上调。达特是HIV感染细胞产生和释放的一种蛋白质，可能在HIV感染过程中的脑血管病理中发挥重要作用。在MRP家族中，暴露于达特特异性诱导BMEC和星形胶质细胞中的MRP 1信使核糖核酸和蛋白质表达。这些改变伴随着增强的MRP 1介导的外排功能。此外，丝裂原活化蛋白激酶信号级联的激活被确定为参与Tat介导的MRP 1过表达的机制。这些结果表明，达特暴露可导致BBB功能的改变，并通过药物外排转运蛋白的过表达降低CNS中的HAART功效。
Central nervous system (CNS) complications of human immunodeficiency virus (HIV) infection remain a serious health risk in HIV/acquired immunodeficiency syndrome despite significant advances in highly active antiretroviral therapy (HAART). Specific drugs used for HAART are substrates for the efflux transport systems, such as the multidrug resistance-associated proteins (MRPs), which are present on brain microvascular endothelial cells (BMEC) and astrocytes, that is, the main cell types that form the blood-brain barrier (BBB). Thus, drugs employed in HAART are actively removed from the CNS and do not efficiently inhibit HIV replication in the brain. To study the potential mechanisms of this process, the aim of the present research was to address the hypothesis that HIV Tat protein can contribute to upregulation of MRP expression at the BBB level. Tat is a protein produced and released by HIV-infected cells, which may play an important role in brain vascular pathology in the course of HIV infection. Among the family of MRPs, exposure to Tat specifically induced MRP1 messenger ribonucleic acid and protein expression both in BMEC and astrocytes. These alterations were accompanied by enhanced MRP1-mediated efflux functions. Furthermore, activation of the mitogen-activated protein kinase signaling cascade was identified as the mechanism involved in Tat-mediated overexpression of MRP1. These results indicate that Tat exposure can lead to alterations of the BBB functions and decrease HAART efficacy in the CNS through overexpression of drug efflux transporters.