Department of Immunology and Nano-medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, 33199, USA.
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, Virginia, USA.
J Neurovirol. 2019 Apr;25(2):263-274. doi: 10.1007/s13365-018-0715-4. Epub 2019 Feb 11.
Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure. The effect of the protease inhibitor, lopinavir, alone or in combination with the protease inhibitor, abacavir, and the integrase inhibitor, raltegravir (LAR), with and without morphine co-exposure was also explored. Exposure with emtricitabine alone or ERA in HIV-infected astrocytes caused a significant decrease in viral replication and attenuated HIV-induced inflammatory molecules, while co-exposure with morphine negated the inhibitory effects of ERA, leading to increased viral replication and inflammatory molecules. Exposure with emtricitabine alone or in combination with morphine caused a significant disruption of mitochondrial membrane integrity. Genetic analysis revealed a significant increase in the expression of p62/SQSTM1 which correlated with an increase in the histone-modifying enzyme, ESCO2, after exposure with ERA alone or in combination with morphine. Furthermore, several histone-modifying enzymes such as CIITA, PRMT8, and HDAC10 were also increased with LAR exposure alone or in combination with morphine. Accumulation of p62/SQSTM1 is indicative of dysfunctional lysosomal fusion. Together with the loss of mitochondrial integrity and epigenetic changes, these effects may lead to enhanced viral titer and inflammatory molecules contributing to the neuropathology associated with HIV.
加速性神经紊乱在 HIV 感染者中越来越突出，可能是由长期使用抗逆转录病毒药物的毒性引起的。我们研究了 HIV 感染的原代人脑星形胶质细胞中抗逆转录病毒药物的潜在副作用，以及阿片类药物共暴露是否会加剧这种反应。将 HIV 感染的人星形胶质细胞暴露于逆转录酶抑制剂恩曲他滨中，单独或与蛋白酶抑制剂利托那韦和阿扎那韦（ERA）联合使用，同时或不与吗啡共暴露。还研究了蛋白酶抑制剂洛匹那韦单独或与蛋白酶抑制剂阿巴卡韦和整合酶抑制剂拉替拉韦（LAR）联合使用，同时或不与吗啡共暴露的情况。在 HIV 感染的星形胶质细胞中单独暴露于恩曲他滨或 ERA 会导致病毒复制显著减少，并减弱 HIV 诱导的炎症分子，而与吗啡共暴露则否定了 ERA 的抑制作用，导致病毒复制和炎症分子增加。单独暴露于恩曲他滨或与吗啡共暴露会导致线粒体膜完整性严重受损。基因分析显示，p62/SQSTM1 的表达显著增加，这与单独暴露于 ERA 或与吗啡共暴露后组蛋白修饰酶 ESCO2 的增加相关。此外，单独暴露于 LAR 或与吗啡共暴露后，几种组蛋白修饰酶，如 CIITA、PRMT8 和 HDAC10 的表达也增加。p62/SQSTM1 的积累表明溶酶体融合功能失调。与线粒体完整性的丧失和表观遗传变化一起，这些影响可能导致病毒滴度和炎症分子增加，从而导致与 HIV 相关的神经病理学。
