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首页> 外文期刊>Journal of neuroinflammation >Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment
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Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment

机译：小胶质细胞激活减少蛋白酶抑制剂沙奎那韦的保留：对HIV治疗的影响

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Background Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide. Methods To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS). Results [3H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters. Conclusions The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-κβ and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site.
机译：背景技术中枢神经系统（CNS）中的主动HIV感染主要限于小胶质细胞。胶质细胞隔室充当血脑屏障后面的病毒库。它通过多种药物外排转运蛋白（包括P-糖蛋白）的表达为有效药理治疗提供了额外的障碍。 HIV / AIDS患者经常遭受细菌和病毒的合并感染，导致神经胶质细胞功能失调并释放促炎性介质，包括细胞因子，趋化因子和一氧化氮。方法为了更好地确定炎症在减少HIV药物向CNS靶标积累中的作用，在暴露于原型炎症介质脂多糖（LPS）的啮齿动物小胶质细胞的纯化培养物中检测了抗逆转录病毒沙奎那韦的积累。结果[3H]-沙奎那韦在小胶质细胞中蓄积迅速，在特定P-糖蛋白抑制剂PSC833的存在下，蓄积可增加至两倍。暴露于10 ng / ml LPS 6或24小时后，沙奎那韦的蓄积量最多降低了45％。 LPS不直接抑制沙奎那韦转运，也不影响P-糖蛋白蛋白表达。暴露于LPS不会改变其他转运蛋白的RNA和/或蛋白质表达，包括与多药耐药相关的蛋白1和几种溶质载体摄取转运蛋白。结论LPS治疗后小胶质细胞中saquinavir积累的减少可能是多因素的，因为小胶质细胞HAPI以及通行费像受体4缺陷的小鼠。这些数据为为什么小胶质细胞充当难以治疗的病毒庇护所提供了新的药理学见识。

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