Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

尽管通过抗逆转录病毒疗法(ART)有效地控制了病毒，但艾滋病毒相关性神经认知障碍(HAND) 在30%-50%的患者中持续存在。在艺术时代，神经病理学已经从快速发展的 脑性疾病是一种长期的神经退行性疾病，其病理特征包括 星形胶质细胞增多症、小胶质细胞增多症、树突状细胞损伤，尤其是脑白质缺陷症。脑白质改变 包括髓鞘厚度减少、髓鞘病变和髓鞘蛋白异常表达。这个 脑白质损伤的严重程度与接受ART治疗的时间长短相关。转录组分析 接受抗逆转录病毒治疗的HIV患者显示与少突胶质细胞成熟和 髓鞘形成。使用一个特性良好的少突胶质细胞培养模型，我们最近报道了 ART中具有代表性的酶抑制剂类药物(利托那韦和洛比那韦)可抑制分化。 少突胶质细胞前体细胞以剂量依赖的方式向成熟少突胶质细胞分化，不依赖于细胞 死亡。给小鼠静脉注射利托那韦仅两周可显著降低该基因的表达 几种髓鞘蛋白。此外，HIV患者大脑皮质中的髓鞘碱性蛋白(MBP)显著减少 正在接受ART并展示手部的患者。这些发现是第一次在一个 实验水平表明，ART可以干扰髓鞘的发育和维持。我们假设艺术 化合物改变少突胶质细胞的分化、功能和存活，有助于手部的持久性。 在后艺术时代。我们新的初步数据表明，核苷类药物的一部分逆转了 转录酶抑制因子(NRTI)类和整合酶抑制因子类也可减少少突胶质细胞 体外分化。在这项提案中，我们将使用我们的少突胶质细胞培养系统来鉴定 抗逆转录病毒药物降低少突胶质细胞成熟的机制，包括脂质调节和细胞 少突胶质细胞中的应激途径，调节髓鞘膜的生成。这样做的第二个目的是 一项提案将研究抗逆转录病毒药物是否可以阻止脱髓鞘侮辱后的再髓鞘形成，使用小剂量 人类免疫缺陷病毒诱导的神经炎症动物模型和脱髓鞘的铜比林模型。第三个目标将是 使用图像分析比较我们的啮齿动物模型与人类患者脑白质的变化。结果来自 这些目标应该有助于设计出更合理的、没有髓鞘缺陷的药物疗法，以减少手痛。

Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND) persists in 30-50% of patients. In the ART era, neuropathology has shifted from a rapidly progressing encephalitic condition to a prolonged neurodegenerative disease with pathologic features including astrogliosis, microgliosis, dendritic damage, and especially white matter deficits. White matter alterations include decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. The severity of white matter damage correlates with the amount of time on ART therapy. Transcriptome analysis of HIV patients on ART revealed decreases in genes associated with oligodendrocyte maturation and myelination. Using a well-characterized oligodendrocyte culture model, we have recently reported that representative drugs from the protease inhibitor class of ART (ritonavir and lopinavir) inhibit differentiation of oligodendrocyte precursors to mature oligodendrocytes in a dose-dependent manner, independent of cell death. Intravenous administration of ritonavir to mice for only two weeks significantly decreased the expression of several myelin proteins. Further, myelin basic protein (MBP) was significantly decreased in the cortex of HIV patients who were on ART and exhibited HAND. These findings are the first to demonstrate on an experimental level that ART can disrupt myelin development and maintenance. We hypothesize that ART compounds alter oligodendrocyte differentiation, function, and survival, contributing to the persistence of HAND in the post-ART era. Our new preliminary data suggest that a subset of drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class and from the integrase inhibitor class also decrease oligodendrocyte differentiation in vitro. In this proposal, we will use our oligodendrocyte cell culture system to identify mechanisms by which ART drugs decrease oligodendrocyte maturation, including lipid regulation and cellular stress pathways in oligodendrocytes, which regulate myelin membrane generation. The second aim of this proposal will examine whether ART drugs can impede remyelination after a demyelinating insult using small animal model of HIV-induced neuroinflammation and the cuprizone model of demyelination. The third aim will compare white matter changes in our rodent model with human patients using image analysis. Results from these aims should help devise more rational drug therapies without myelin deficits to reduce HAND.