HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes
HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes
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DOI：
10.1073/pnas.0611699104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Berman, Joan W.
中科院分区：
文献类型：
--
作者：
Eugenin, Eliseo A.;King, Jessie E.;Berman, Joan W.
中枢神经系统的HIV感染可导致神经功能障碍，对AIDS患者造成毁灭性后果。NeuroAIDS的特征是神经元损伤和损失，但没有证据表明HIV可以感染神经元。在这里，我们表明，艾滋病毒编码的蛋白质达特触发形成一个大分子复合物，涉及低密度脂蛋白受体相关蛋白（LRP），突触后密度蛋白-95（PSID-95），N-甲基-D-天冬氨酸（NMDA）受体，和神经元一氧化氮合酶（nNOS）在神经元质膜，这种复合物导致NMDA受体阴性和阳性神经元以及星形胶质细胞的凋亡。阻断LR-P介导的达特摄取、NMDA受体激活或神经元型一氧化氮合酶可显著减少随后的神经元凋亡，表明该复合物的形成是达特毒性的早期步骤。我们还表明，炎症趋化因子，CCL 2，防止达特毒性和抑制复合物的形成。这些研究结果牵连复杂的艾滋病毒诱导的神经细胞凋亡，并建议干预神经艾滋病的发病机制的治疗目标。
HIV infection of the central nervous system can result in neurologic dysfunction with devastating consequences in AIDS patients. NeuroAIDS is characterized by neuronal injury and loss, yet there is no evidence that HIV can infect neurons. Here we show that the HIV-encoded protein tat triggers formation of a macromolecular complex involving the low-density lipoprotein receptor-related protein (LRP), postsynaptic density protein-95 (PSID-95), N-methyl-D-aspartic acid (NMDA) receptors, and neuronal nitric oxide synthase (nNOS) at the neuronal plasma membrane, and that this complex leads to apoptosis in neurons negative as well as positive for NMDA receptors and also in astrocytes. Blockade of LR-Pmediated tat uptake, NMDA receptor activation, or neuronal nitric oxide synthase significantly reduces ensuing neuronal apoptosis, suggesting that formation of this complex is an early step in tat toxicity. We also show that the inflammatory chemokine, CCL2, protects against tat toxicity and inhibits formation of the complex. These findings implicate the complex in HIV-induced neuronal apoptosis and suggest therapeutic targets for intervention in the pathogenesis of NleuroAIDS.