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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：
10609743
负责人：
JUDITH B GRINSPAN
金额：
$ 11.04万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10609743
关键词：
Animal Model Brain Cell Culture System Cell Death Cellular Stress Cuprizone Data Demyelinations Development Dose Exhibits Functional disorder Generations Genes HIV HIV Infections HIV Seropositivity HIV-associated neurocognitive disorder Human Image Analysis In Vitro Integrase Inhibitors Lesion Lipids Lopinavir Maintenance Membrane Modeling Mus Myelin Myelin Basic Proteins Myelin Proteins Myelin Sheath Neurodegenerative Disorders Nucleosides Oligodendroglia Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Protease Inhibitor Regulation Reporting Reverse Transcriptase Inhibitors Ritonavir Rodent Model Severities Thick Time Viral antiretroviral therapy astrogliosis cell type intravenous administration myelination neuroinflammation neuropathology oligodendrocyte precursor protein expression remyelination transcriptome white matter white matter change white matter damage

项目摘要

Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND) persists in 30-50% of patients. In the ART era, neuropathology has shifted from a rapidly progressing encephalitic condition to a prolonged neurodegenerative disease with pathologic features including astrogliosis, microgliosis, dendritic damage, and especially white matter deficits. White matter alterations include decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. The severity of white matter damage correlates with the amount of time on ART therapy. Transcriptome analysis of HIV patients on ART revealed decreases in genes associated with oligodendrocyte maturation and myelination. Using a well-characterized oligodendrocyte culture model, we have recently reported that representative drugs from the protease inhibitor class of ART (ritonavir and lopinavir) inhibit differentiation of oligodendrocyte precursors to mature oligodendrocytes in a dose-dependent manner, independent of cell death. Intravenous administration of ritonavir to mice for only two weeks significantly decreased the expression of several myelin proteins. Further, myelin basic protein (MBP) was significantly decreased in the cortex of HIV patients who were on ART and exhibited HAND. These findings are the first to demonstrate on an experimental level that ART can disrupt myelin development and maintenance. We hypothesize that ART compounds alter oligodendrocyte differentiation, function, and survival, contributing to the persistence of HAND in the post-ART era. Our new preliminary data suggest that a subset of drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class and from the integrase inhibitor class also decrease oligodendrocyte differentiation in vitro. In this proposal, we will use our oligodendrocyte cell culture system to identify mechanisms by which ART drugs decrease oligodendrocyte maturation, including lipid regulation and cellular stress pathways in oligodendrocytes, which regulate myelin membrane generation. The second aim of this proposal will examine whether ART drugs can impede remyelination after a demyelinating insult using small animal model of HIV-induced neuroinflammation and the cuprizone model of demyelination. The third aim will compare white matter changes in our rodent model with human patients using image analysis. Results from these aims should help devise more rational drug therapies without myelin deficits to reduce HAND.

尽管抗逆转录病毒治疗（ART）有效控制病毒，但HIV相关神经认知障碍（HAND）