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

基本信息

批准号：
9085413
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9085413
关键词：
Adult Anti-Retroviral Agents Antioxidants Behavioral Brain Cell Death Cells Clinical Trials Cognitive Corpus Callosum Cuprizone Demyelinations Development Dose Esters Figs - dietary Fumaric acid Functional disorder Genes HIV HIV Infections HIV Seropositivity HIV antiretroviral HIV-associated neurocognitive disorder In Vitro Incidence Infection Ingestion Macaca nemestrina Maintenance Modeling Morphology Multiple Sclerosis Mus Myelin 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 motor disorder myelination neuropathology oligodendrocyte lineage oligodendrocyte myelination oligodendrocyte precursor oxidative damage precursor cell remyelination repaired response transcriptome white matter white matter change white matter damage white matter injury

项目摘要

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）导致最严重的HIV相关神经认知障碍（Hand）的发生率显着降低。但是，据报道，严重严重的认知，行为和运动功能障碍的水平持续存在30-50％的患者。与HIV相关的神经病理学已从迅速发展的脑疾病转变为长时间的神经退行性疾病，具有病理特征，包括星形胶质细胞增多，小胶质细胞增多症和树突状损害。但是，白质变化仍然是在艺术前和艺术后时代的共同特征。有趣的是，最近的转录组分析表明，在未经治疗的手和用ART治疗的手动治疗的患者中，与少突胶质分化和髓磷脂产生相关的基因受到调节。这些发现表明，艾滋病毒和艺术可能会破坏髓磷脂的发育和维护。但是，尚未研究单独或与HIV感染细胞对少突胶质细胞及其前体细胞结合的作用。我们假设艺术化合物改变了少突胶质细胞的分化，功能和生存，这有助于在艺术后时代的持续存在。为此，我们已经证明了2种抗逆转录病毒化合物（ARV），一个核苷逆转录酶抑制剂（NRTI），AZT和一个蛋白酶抑制剂（PI），利托纳维尔，改变寡胶质细胞的形态，并降低寡头胶质细胞的生存。此外，在无毒性浓度下，AZT和利托那韦破坏了体外诱导氧化损伤的少突胶质细胞前体（OPC）的成熟，并诱导内源性抗氧化剂反应，如血红素氧酶1（HO1）的上调所示。氧化应激已显示可改变围产期白质损伤和多发性硬化症模型中的少突胶质细胞存活和分化。最近的一项研究表明，在MS临床试验中，具有抗氧化特性的富马酸酯（FAE）有效。鉴于在有手的患者中有氧化应激的存在，包括在ART的患者中，我们建议测试HIV感染的巨噬细胞（HIVMDM）和ARV化合物的假设，可诱导氧化应激改变少突胶质细胞分化，功能，功能和生存率。为了进行测试，我们将：a）确定HIVMDM和ARV对成熟少突胶质细胞的发展和维持的贡献，b）确定HIVMDM和ARV诱导的氧化应激在阻断少突胶质细胞差异和髓鞘中的氧化应激的作用，在慢病毒感染和灵长类动物中的背景下，少突胶质细胞损伤和压力。