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: 8511840
• 负责人: JUDITH B GRINSPAN
• 金额: $ 51.13万
• 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/8511840
• 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）已导致最严重形式的HIV相关神经认知障碍（HAND）的发生率显著降低;然而，据报道，30-50%的患者持续存在较不严重形式的认知、行为和运动功能障碍。HIV相关的神经病理学已经从快速进展的脑炎状况转变为具有病理特征的长期神经退行性疾病，包括星形胶质细胞增生、小胶质细胞增生和树突状细胞损伤。然而，白色物质的变化仍然是前ART时代和后ART时代HAND的共同特征。有趣的是，最近的一项转录组分析表明，与少突胶质细胞分化和髓鞘生产相关的基因在未经治疗的HAND患者以及接受ART治疗的HAND患者中下调。这些发现表明，HIV和ART可能会破坏髓鞘的发育和维持。然而，ART化合物单独或与HIV感染的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化合物改变少突胶质细胞的分化，功能和存活，有助于后ART时代HAND的持续存在。为此，我们已经证明，2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，改变少突胶质细胞的形态和减少少突胶质细胞的存活在体外剂量依赖性的方式。此外，在亚毒性浓度下，AZT和利托那韦在体外破坏少突胶质细胞前体（OPCs）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（HO 1）上调所示。在围产期白色物质损伤和多发性硬化模型中，氧化应激已被证明可改变少突胶质细胞的存活和分化。最近的一项研究表明，富马酸酯（FAE）具有抗氧化性能是有效的MS临床试验。考虑到HAND患者（包括ART患者）CNS中存在氧化应激，我们建议检验HIV感染的巨噬细胞（HIVMDM）和ARV化合物诱导氧化应激改变体外和体内少突胶质细胞分化、功能和存活的假设。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的发育和维持的贡献，B）确定HIVMDM和ARV诱导的氧化应激在阻断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，和d）确定灵长类动物中在慢病毒感染和ART的情况下少突胶质细胞损伤和应激的状态。