Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

描述(由申请人提供)： 抗逆转录病毒疗法(ART)显著降低了最严重形式的艾滋病毒相关神经认知障碍(HAND)的发病率；然而，据报道，30%-50%的患者持续存在较轻形式的认知、行为和运动功能障碍。HIV相关的神经病理学已经从快速发展的脑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症、小胶质细胞增多症和树突损伤。然而，在艺术之前和之后的时代，白质变化仍然是手的一个共同特征。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产生相关的基因在未经治疗的手部患者以及接受ART治疗的手部患者中下调。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鞘的发育和维持。然而，ART化合物单独或与HIV感染细胞联合使用对少突胶质细胞及其前体细胞的影响尚未被研究。我们假设，ART化合物改变了少突胶质细胞的分化、功能和生存，有助于手在后ART时代的持续存在。为此，我们已经证明了两种抗逆转录病毒化合物(ARV)、一种核苷类逆转录酶抑制剂(NRTI)AZT和一种蛋白酶抑制剂(PI)利托那韦在体外以剂量依赖的方式改变少突胶质细胞的形态并降低少突胶质细胞的存活率。此外，在亚毒性浓度下，AZT和利托那韦均可阻断体外培养的少突胶质细胞前体细胞(OPC)的成熟，诱导氧化损伤，并诱导内源性抗氧化反应，如上调血红素加氧酶1(HO1)所示。在围产期白质损伤和多发性硬化症模型中，氧化应激都被证明改变了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)具有抗氧化特性，在MS临床试验中是有效的。鉴于手部患者(包括ART患者)中枢神经系统存在氧化应激，我们建议检验HIV感染巨噬细胞(HIVMDM)和ARV化合物诱导氧化应激改变少突胶质细胞的分化、功能和存活的假说。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，以及d)在慢病毒感染和灵长类动物抗逆转录病毒治疗的背景下确定少突胶质细胞的损伤和应激状态。 公共卫生相关性： 尽管出现了抗逆转录病毒治疗，但艾滋病毒阳性患者的脑白质继续发生变化。负责形成和维持白质的细胞类型是少突胶质细胞。我们的研究将评估HIV感染和抗逆转录病毒治疗对HIV阳性患者脑白质变化的影响。

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. PUBLIC HEALTH RELEVANCE: Despite the advent of antiretroviral therapy, HIV positive patients continue to have changes in the white matter of the brain. The cell type responsible for forming and maintaining white matter is the oligodendrocyte. Our study will assess the effects of HIV -infection and antiretroviral therapy on changes in white matter in HIV- positive patients.