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: 8698817
• 负责人: JUDITH B GRINSPAN
• 金额: $ 53.26万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698817
• 关键词: Adult; Anti-Retroviral Agents; Antioxidants; Behavioral; Brain; Cell Death; Cells; Clinical Trials; Cognitive; Corpus Callosum; Cuprizone; Demyelinations; Development; Disease; Dose; Esters; Figs - dietary; Fumaric acid; Functional disorder; Gene Expression Profile; Genes; HIV; HIV Infections; HIV Seropositivity; In Vitro; Incidence; Infection; Ingestion; Macaca nemestrina; Maintenance; Modeling; Morphology; Motor; Multiple Sclerosis; Mus; Myelin; Neurocognitive; Neurodegenerative Disorders; Nucleosides; Oligodendroglia; Oxidative Stress; Pathologic; Pathway interactions; Patients; Perinatal; Pharmaceutical Preparations; Population; Primates; Production; Property; Protease Inhibitor; Reporting; Reverse Transcriptase Inhibitors; Ritonavir; Role; SIV; Stress; Testing; Up-Regulation; Virus Diseases; Zidovudine; antiretroviral therapy; astrogliosis; cell type; clinically relevant; heme oxygenase-1; in vivo; macrophage; myelination; neuropathology; oligodendrocyte lineage; oligodendrocyte precursor; oxidative damage; precursor cell; remyelination; repaired; response; white matter; white matter change; white matter damage; white matter injury

DESCRIPTION (provided by applicant): Antiretroviral therapy (ART) has led to significant decrease in incidence of the most severe forms of HIV associated neurocognitive disorder (HAND); however, the level of less severe forms of cognitive, behavioral and motor dysfunction have been reported to persist in 30-50% of patients. HIV-associated neuropathology has shifted from a rapidly progressing encephalitic condition to a prolonged neurodegenerative disease with pathologic features including astrogliosis, microgliosis and dendritic damage. However, white matter changes remain a common feature of HAND in the pre- and post-ART era. Intriguingly, a recent transcriptome analysis has shown that genes associated with oligodendrocyte differentiation and myelin production are down regulated in untreated patients with HAND as well as in patients with HAND treated with ART. These findings indicate that HIV and ART may disrupt myelin development and maintenance. However, the effects of ART compounds alone or in combination with HIV-infected cells on the oligodendrocytes and their precursor cells have not been studied. We hypothesize, that ART compounds alter oligodendrocyte differentiation, function, and survival, contributing to the persistence of HAND in the post-ART era. To this end, we have demonstrated that 2 antiretroviral compounds (ARV), one nucleoside reverse transcriptase inhibitor (NRTI), AZT, and one protease inhibitor (PI), ritonavir, alter oligodendrocyte morphology and decrease oligodendrocyte survival in a dose dependent manner in vitro. Further, at subtoxic concentrations, both AZT and ritonavir disrupt maturation of oligodendrocyte precursors (OPCs) in vitro induce oxidative damage and induce the endogenous antioxidant response as indicated by upregulation of heme oxygenase 1 (HO1). Oxidative stress has been shown to alter oligodendrocyte survival and differentiation in both perinatal white matter injury and Multiple Sclerosis models. A recent study has shown that a fumaric acid ester (FAE) with antioxidant properties is efficacious in MS clinical trials. Given th presence of oxidative stress in the CNS of patients with HAND, including those on ART we propose to test the hypothesis that HIV-infected macrophages (HIVMDM) and ARV compounds induce oxidative stress altering oligodendrocyte differentiation, function, and survival in vitro ad in vivo. To test this we will: a) determine the contribution of HIVMDM and ARVs to the development and maintenance of mature oligodendrocytes, b) determine the role of HIVMDM- and ARV-induced oxidative stress in blocking oligodendrocyte differentiation and myelination, c) determine the effect of ARV-induced oxidative stress on oligodendrocytes in vivo, and d) determine the state of oligodendrocyte damage and stress in the context of lentiviral-infection and ART in primates.

描述（由申请人提供）： 抗逆转录病毒疗法 (ART) 显着降低了最严重的 HIV 相关神经认知障碍 (HAND) 的发病率；然而，据报道，30-50% 的患者仍存在不太严重的认知、行为和运动功能障碍。 HIV相关的神经病理学已从一种快速进展的脑炎疾病转变为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生、小胶质细胞增生和树突状损伤。然而，白质变化仍然是 ART 前后 HAND 的一个共同特征。有趣的是，最近的转录组分析表明，在未经治疗的 HAND 患者以及接受 ART 治疗的 HAND 患者中，与少突胶质细胞分化和髓磷脂生成相关的基因下调。这些发现表明，艾滋病毒和抗逆转录病毒治疗可能会破坏髓磷脂的发育和维持。然而，ART化合物单独或与HIV感染细胞组合对少突胶质细胞及其前体细胞的影响尚未研究。我们假设，ART 化合物会改变少突胶质细胞的分化、功能和存活，从而有助于 HAND 在后 ART 时代的持续存在。为此，我们证明了两种抗逆转录病毒化合物（ARV）、一种核苷逆转录酶抑制剂（NRTI）AZT和一种蛋白酶抑制剂（PI）利托那韦在体外以剂量依赖性方式改变少突胶质细胞形态并降低少突胶质细胞存活率。此外，在亚毒性浓度下，AZT 和利托那韦都会破坏体外少突胶质细胞前体 (OPC) 的成熟，诱导氧化损伤并诱导内源性抗氧化反应，如血红素加氧酶 1 (HO1) 上调所示。在围产期白质损伤和多发性硬化症模型中，氧化应激已被证明会改变少突胶质细胞的存活和分化。最近的一项研究表明，具有抗氧化特性的富马酸酯 (FAE) 在 MS 临床试验中有效。鉴于 HAND 患者（包括接受 ART 的患者）中枢神经系统存在氧化应激，我们建议检验以下假设：HIV 感染的巨噬细胞 (HIVMDM) 和 ARV 化合物诱导氧化应激改变少突胶质细胞的体外和体内分化、功能和存活。为了测试这一点，我们将：a）确定 HIVMDM 和 ARV 对成熟少突胶质细胞发育和维持的贡献，b）确定 HIVMDM 和 ARV 诱导的氧化应激在阻止少突胶质细胞分化和髓鞘形成中的作用，c）确定 ARV 诱导的氧化应激对体内少突胶质细胞的影响，d）确定 灵长类动物慢病毒感染和 ART 背景下的少突胶质细胞损伤和应激。