HIV latency in astrocytes

HIV在星形胶质细胞中的潜伏期

• 批准号: 8487988
• 负责人: Lena Al-Harthi
• 金额: $ 45.66万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487988
• 关键词: AIDS neuropathy; Acute; Address; Antiviral Agents; Astrocytes; Attention; Automobile Driving; Blood Cells; Brain; CD4 Positive T Lymphocytes; Cells; Conditioned Culture Media; DNA; Data; Epigenetic Process; Equilibrium; Evolution; Exhibits; Genetic; Glycoproteins; HIV; HIV Infections; Hematopoietic; Infection; Invaded; Knowledge; Leukocytes; Ligands; Lymphoid Tissue; Microglia; Modification; Molecular; Neuraxis; Output; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Positioning Attribute; Publishing; Residual state; Rest; Role; Severities; Signal Pathway; Signal Transduction; Site; T-Lymphocyte; Therapeutic; Tissues; Virus; antiretroviral therapy; base; brain cell; cell type; cohort; defined contribution; macrophage; monocyte; novel; public health relevance; purge

DESCRIPTION (provided by applicant): HIV invades the CNS during acute infection and persists in the brain despite combination antiretroviral therapy. The cellular and molecular mechanisms of HIV latency in the brain are not entirely clear. Data from our lab and that of others indicate that astrocytes, which constitute 50-70% of brain cells, are reservoirs for HIV exhibiting several important features defining HIV reservoirs. Yet little is known about the molecular mechanism(s) driving HIV latency in astrocytes and the extent of HIV compartmentalization within astrocytes. To address some of these knowledge gaps, we will define the epigenetic modifications of HIV DNA that drive latency in astrocytes and compare how these modifications are different or similar to those engaged by other HIV infected resident brain cells (macrophages/microglia) and within resting CD4+ T cells. Further, while there are extensive studies documenting HIV compartmentalization in the CNS, there is little evidence for the extent of HIV compartmentalization in astrocytes and its association with severity of HAND. We will assess the extent of HIV compartmentalization in astrocytes and its relationship to HIV from macrophages/microglia and correlation with various degrees of HAND. Finally, we will better define a novel dual role for astrocytes in NeuroAIDS that potentially regulates the extent of HIV latency in the CNS. We previously demonstrated that while astrocytes support HIV infection, they restrict virus output unless the Wnt/b-catenin signaling pathway is disrupted (e.g. inhibition of Wnt/b- catenin signaling in astrocytes leads to productive HIV replication). We provide preliminary data to indicate that astrocytes secrete specific Wnt ligands (soluble glycoproteins that initiate the Wnt/b-catenin pathway) to limit HIV replication in infiltrating peripheral blood mononuclear cells (PBMCs). We will define the role of Wnt ligands in suppression of HIV in leukocytes and establish the mechanism by which they do so. Collectively, these studies are critical to inform better therapeutic strategies to tackle the challenge of HIV latency in the CNS.

描述（由申请人提供）：HIV在急性感染期间侵入中枢神经系统，尽管结合了抗逆转录病毒疗法，但在大脑中持续存在。大脑中艾滋病毒潜伏期的细胞和分子机制尚不完全清楚。来自我们实验室和其他实验室的数据表明，构成50-70％脑细胞的星形胶质细胞是HIV的储层，这些储层表现出定义HIV储层的几个重要特征。然而，对于驱动星形胶质细胞中艾滋病毒潜伏期的分子机制和星形胶质细胞内的HIV分区化程度知之甚少。为了解决这些知识差距中的一些，我们将定义HIV DNA的表观遗传修饰，这些修饰驱动星形胶质细胞的潜伏期，并比较这些修饰与其他HIV感染的HIV感染的居民脑细胞（巨噬细胞/微胶质细胞）以及静息CD4+ T细胞的不同或相似。此外，尽管有广泛的研究记录了中枢神经系统中的HIV分区化，但几乎没有证据表明星形胶质细胞中HIV隔室化的程度及其与手的严重性相关。我们将评估星形胶质细胞中HIV分区的程度及其与巨噬细胞/小胶质细胞与HI​​V的关系，以及与各种手的相关性。最后，我们将更好地定义星形胶质细胞在神经辅助中的新型双重作用，该角色可能调节中枢神经系统中艾滋病毒潜伏期的程度。我们先前证明，尽管星形胶质细胞支持HIV感染，但除非破坏Wnt/B-catenin信号通路，否则它们会限制病毒的输出（例如，抑制星形胶质细胞中Wnt/B- catenin信号传导会导致生产性HIV复制）。我们提供初步数据，以表明星形胶质细胞分泌特定的Wnt配体（启动Wnt/B-catenin途径的可溶性糖蛋白）以限制浸润性外周血单核细胞（PBMC）中浸润性HIV复制。我们将定义Wnt配体在白细胞中抑制HIV中的作用，并确定它们这样做的机制。总的来说，这些研究对于为更好的治疗策略提供了至关重要的研究，以应对中枢神经系统中艾滋病毒潜伏期的挑战。