Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

HIV相关神经认知障碍中的少突胶质细胞损伤和功能障碍

• 批准号: 10609743
• 负责人: JUDITH B GRINSPAN
• 金额: $ 11.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609743
• 关键词: Animal Model; Brain; Cell Culture System; Cell Death; Cellular Stress; Cuprizone; Data; Demyelinations; Development; Dose; Exhibits; Functional disorder; Generations; Genes; HIV; HIV Infections; HIV Seropositivity; HIV-associated neurocognitive disorder; Human; Image Analysis; In Vitro; Integrase Inhibitors; Lesion; Lipids; Lopinavir; Maintenance; Membrane; Modeling; Mus; Myelin; Myelin Basic Proteins; Myelin Proteins; Myelin Sheath; Neurodegenerative Disorders; Nucleosides; Oligodendroglia; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Protease Inhibitor; Regulation; Reporting; Reverse Transcriptase Inhibitors; Ritonavir; Rodent Model; Severities; Thick; Time; Viral; antiretroviral therapy; astrogliosis; cell type; intravenous administration; myelination; neuroinflammation; neuropathology; oligodendrocyte precursor; protein expression; remyelination; transcriptome; white matter; white matter change; white matter damage

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.

尽管抗逆转录病毒疗法（ART）有效控制了病毒，但艾滋病毒相关的神经认知障碍（HAND） 在30-50%的患者中持续存在。在ART时代，神经病理学已经从一个快速发展的 从脑炎到长期神经退行性疾病的病理特征，包括 星形胶质细胞增生、小胶质细胞增生、树突损伤，尤其是白色物质缺乏。白色物质改变 包括髓鞘厚度减少、髓鞘损伤和异常髓鞘蛋白表达。的 白色物质损伤的严重程度与ART治疗的时间量相关。转录组分析 接受抗逆转录病毒治疗的艾滋病患者显示，与少突胶质细胞成熟相关的基因减少， 髓鞘形成我们最近报道，使用一种特征良好的少突胶质细胞培养模型， 来自ART的蛋白酶抑制剂类的代表性药物（利托那韦和洛匹那韦）抑制 少突胶质细胞前体以剂量依赖性方式向成熟少突胶质细胞转化，不依赖于细胞 死亡给小鼠静脉注射利托那韦仅两周， 几种髓磷脂蛋白质。此外，髓鞘碱性蛋白（MBP）显着减少，在皮质的艾滋病毒 接受抗逆转录病毒治疗并出现手征的患者。这些发现是第一个证明在一个 在实验水平上，ART可以破坏髓鞘的发育和维持。我们假设ART 化合物改变少突胶质细胞的分化、功能和存活，有助于HAND的持续存在。 在后ART时代。我们的新的初步数据表明，一个子集的药物从核苷逆转 转录酶抑制剂（NRTI）类和整合酶抑制剂类也减少少突胶质细胞 体外分化。在这个提议中，我们将使用我们的少突胶质细胞培养系统来鉴定 ART药物降低少突胶质细胞成熟的机制，包括脂质调节和细胞凋亡。 少突胶质细胞中的应激途径，其调节髓鞘膜的生成。第二个目的是 一项提案将研究ART药物是否能阻止脱髓鞘损伤后的髓鞘再生， HIV诱导的神经炎症的动物模型和脱髓鞘的铜腙模型。第三个目标将 使用图像分析比较我们的啮齿动物模型与人类患者的白色物质变化。结果 这些目标应该有助于设计出更合理的药物治疗方法，而不需要髓鞘缺陷来减少HAND。