A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia.
A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia.
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DOI：
10.1097/qad.0b013e3283639804
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发表时间：
2013-09-10
期刊：
影响因子：
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通讯作者：
Hauser KF
中科院分区：
文献类型：
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作者：
El-Hage N;Dever SM;Podhaizer EM;Arnatt CK;Zhang Y;Hauser KF
我们探索了阿片类药物吗啡是否会影响马拉韦洛克的作用，以及最近合成的与阿片类拮抗剂纳曲酮相关的马拉韦洛克二价衍生物对HIV-1进入人初级神经胶质的作用。在含有荧光素酶报告基因的LTR构建体瞬时转染的胶质细胞中，HIV-1进入被监测，LTR构建体受HIV-1反激活蛋白Tat启动子的控制。同时探讨马拉韦洛克与二价配体±吗啡对CCR5表面表达及细胞因子释放的影响。马拉维洛克抑制HIV-1进入神经胶质细胞，而吗啡则会抵消马拉维洛克的作用，导致病毒进入的显著增加。我们还证明，与与吗啡共给药相比，含马拉韦洛克的二价配体在星形胶质细胞中比在小胶质细胞中更好地抑制r5型病毒的进入。重要的是，二价化合物对星形胶质细胞的抑制作用不受吗啡的影响。在星形胶质细胞和小胶质细胞中，暴露于马拉韦洛克降低了促炎细胞因子的释放，并限制了hiv -1依赖性CCR5表达的增加，而暴露于二价的马拉韦洛克在星形胶质细胞中有类似的效果，但在小胶质细胞中没有。CCR5-MOR的化学计量比在两种细胞类型之间存在差异，CCR5在小胶质细胞中的表达水平远高于MOR，这可以解释二价配体在星形胶质细胞中的有效性。一种新的二价化合物揭示了神经胶质细胞中CCR5-MOR相互作用和HIV-1感染性的根本差异，并且在阿片类药物滥用- hiv相互作用合并症中具有独特的治疗潜力。
We explored whether the opiate, morphine, affects the actions of maraviroc, as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist, naltrexone, on HIV-1 entry in primary human glia. HIV-1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV-1 transactivator protein Tat. The effect of maraviroc and the bivalent ligand ± morphine on CCR5 surface expression and cytokine release was also explored. Maraviroc inhibits HIV-1 entry into glial cells, while morphine negates the effects of maraviroc leading to a significant increase in viral entry. We also demonstrate that the maraviroc-containing bivalent ligand better inhibits R5-tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine. Importantly, the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine. Exposure to maraviroc decreased the release of pro-inflammatory cytokines and restricted HIV-1-dependent increases in CCR5 expression in both astrocytes and microglia, while exposure to the bivalent had similar effect in astrocytes but not in microglia. CCR5-MOR stoichiometric ratio varied among the two cell types with CCR5 expressed at much higher levels than MOR in microglia, which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia. A novel bivalent compound reveals fundamental differences in CCR5-MOR interactions and HIV-1 infectivity among glia, and has unique therapeutic potential in opiate abuse-HIV interactive comorbidity.