Specific increase in MDR1 mediated drug-efflux in human brain endothelial cells following co-exposure to HIV-1 and saquinavir.
Specific increase in MDR1 mediated drug-efflux in human brain endothelial cells following co-exposure to HIV-1 and saquinavir.
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在同时暴露于 HIV-1 和沙奎那韦后，人脑内皮细胞中 MDR1 介导的药物流出发生特异性增加。
DOI：
10.1371/journal.pone.0075374
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mondal D
中科院分区：
文献类型：
--
作者：
Roy U;Bulot C;Honer zu Bentrup K;Mondal D
HIV-1储存库在中枢神经系统（CNS）内的持久性仍然是对有效抗HIV-1药物有效性的重大挑战。原代人脑微血管内皮细胞（HBMVEC）构成血脑屏障（BBB），干扰抗hiv药物进入中枢神经系统。HBMVEC上表达的ATP结合盒（ABC）转运体可以外排HIV-1蛋白酶抑制剂（HPI），使HIV-1在中枢神经系统中持续存在。几种abc转运蛋白，如MDR1（又名P-gp）和MRPs的组成性低水平表达在HBMVEC中被记录。虽然人们认识到炎症细胞因子和暴露于外源药物底物（如HPI）可以增强这些转运蛋白的表达，但目前尚不清楚同时暴露于病毒和抗逆转录病毒药物是否可以增加HBMVEC的药物外排功能。我们的体外研究表明，HBMVEC暴露于HIV-1显著上调MDR1基因表达和蛋白水平；然而，MRP-1或MRP-2均未见明显升高。此外，利用HBMVEC进行的钙黄蛋白- am染料外排试验显示，与单独暴露于病毒相比，同时暴露于HIV-1和沙奎那韦（SQV）后，MDR1介导的药物外排功能显著诱导。MDR1介导的药物外排的增加通过放射性标记的[3H-] SQV细胞内潴留的增加得到进一步证实。MDR1特异性阻滞剂（PSC-833）和MDR1特异性sirna进一步证实了MDR1在HBMVEC 3H-SQV外排中的关键作用。因此，在HIV-1和SQV共同暴露后，HBMVEC中MDR1特异性药物外排功能增加，这可以减少hpi进入HIV-1感染的脑库的渗透。因此，通过增强HAART药物的治疗效果，靶向抑制血脑屏障中的MDR1可能提供一种抑制中枢神经系统中残留病毒复制的新策略。
Persistence of HIV-1 reservoirs within the Central Nervous System (CNS) remains a significant challenge to the efficacy of potent anti-HIV-1 drugs. The primary human Brain Microvascular Endothelial Cells (HBMVEC) constitutes the Blood Brain Barrier (BBB) which interferes with anti-HIV drug delivery into the CNS. The ATP binding cassette (ABC) transporters expressed on HBMVEC can efflux HIV-1 protease inhibitors (HPI), enabling the persistence of HIV-1 in CNS. Constitutive low level expression of several ABC-transporters, such as MDR1 (a.k.a. P-gp) and MRPs are documented in HBMVEC. Although it is recognized that inflammatory cytokines and exposure to xenobiotic drug substrates (e.g HPI) can augment the expression of these transporters, it is not known whether concomitant exposure to virus and anti-retroviral drugs can increase drug-efflux functions in HBMVEC. Our in vitro studies showed that exposure of HBMVEC to HIV-1 significantly up-regulates both MDR1 gene expression and protein levels; however, no significant increases in either MRP-1 or MRP-2 were observed. Furthermore, calcein-AM dye-efflux assays using HBMVEC showed that, compared to virus exposure alone, the MDR1 mediated drug-efflux function was significantly induced following concomitant exposure to both HIV-1 and saquinavir (SQV). This increase in MDR1 mediated drug-efflux was further substantiated via increased intracellular retention of radiolabeled [3H-] SQV. The crucial role of MDR1 in 3H-SQV efflux from HBMVEC was further confirmed by using both a MDR1 specific blocker (PSC-833) and MDR1 specific siRNAs. Therefore, MDR1 specific drug-efflux function increases in HBMVEC following co-exposure to HIV-1 and SQV which can reduce the penetration of HPIs into the infected brain reservoirs of HIV-1. A targeted suppression of MDR1 in the BBB may thus provide a novel strategy to suppress residual viral replication in the CNS, by augmenting the therapeutic efficacy of HAART drugs.
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