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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：
8879215
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879215
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 Gene Expression Profile Genes HIV HIV Infections HIV Seropositivity 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 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）：