Norman John P, Perry Seth W, Reynolds Holly M, Kiebala Michelle, De Mesy Bentley Karen L, Trejo Margarita, Volsky David J, Maggirwar Sanjay B, Dewhurst Stephen, Masliah Eliezer, Gelbard Harris A
Center for Neural Development and Disease, the University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
PLoS One. 2008;3(11):e3731. doi: 10.1371/journal.pone.0003731. Epub 2008 Nov 14.
Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and sustain energy production for normal synaptic communication. In this report, we demonstrate that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor (RyR), followed by the unfolded protein response (UPR) and pathologic dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated both Tat-mediated mitochondrial hyperpolarization and UPR induction. Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic ER dilatation and mitochondrial morphologic abnormalities. Finally, we performed ultrastructural studies that demonstrated mitochondria with abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue of patients with HIV-1 inflammation and neurodegeneration. Collectively, these data suggest that abnormal RyR signaling mediates the neuronal UPR with failure of mitochondrial energy metabolism, and is a critical locus for the neuropathogenesis of HIV-1 in the CNS.
1型人类免疫缺陷病毒（HIV-1）引起的神经疾病最终对高效抗逆转录病毒疗法（HAART）无效，原因是中枢神经系统（CNS）中病毒无法被完全清除，以及病毒诱导的慢性神经炎症破坏了正常的神经信号传导事件。我们之前报道过，HIV-1反式激活转录蛋白（Tat）可诱导皮质神经元中的线粒体超极化，从而损害神经元缓冲钙的能力以及维持正常突触通讯所需的能量产生。在本报告中，我们证明Tat可诱导由兰尼碱受体（RyR）介导的内质网钙快速流失，随后在体外皮质神经元中引发未折叠蛋白反应（UPR）和内质网病理性扩张。RyR拮抗作用可减弱Tat介导的线粒体超极化和UPR诱导。在体内将Tat递送至小鼠CNS也会导致持久的病理性内质网扩张和线粒体形态异常。最后，我们进行了超微结构研究，结果显示在患有HIV-1炎症和神经变性的患者脑组织中，线粒体形态异常且内质网（ER）扩张。总体而言，这些数据表明，异常的RyR信号传导介导了神经元UPR并伴有线粒体能量代谢障碍，并且是HIV-1在CNS中神经发病机制的关键位点。
