HIV latency in astrocytes

描述（由申请人提供）：HIV在急性感染期间侵入CNS，尽管联合抗逆转录病毒治疗，但仍在脑中持续存在。HIV在大脑中潜伏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，占脑细胞50-70%的星形胶质细胞是HIV的储存库，表现出定义HIV储存库的几个重要特征。然而，关于驱动星形胶质细胞中HIV潜伏期的分子机制和星形胶质细胞内HIV区室化的程度知之甚少。为了解决其中的一些知识差距，我们将定义驱动星形胶质细胞潜伏期的HIV DNA的表观遗传修饰，并比较这些修饰与其他HIV感染的常驻脑细胞（巨噬细胞/小胶质细胞）和静息CD内的修饰的不同或相似之处4 + T细胞。此外，虽然有大量研究记录了CNS中的HIV区室化，但几乎没有证据表明星形胶质细胞中的HIV区室化程度及其与HAND严重程度的相关性。我们将评估星形胶质细胞中HIV区室化的程度及其与来自巨噬细胞/小胶质细胞的HIV的关系以及与不同程度的HAND的相关性。最后，我们将更好地定义星形胶质细胞在NeuroAIDS中的新的双重作用，可能调节CNS中HIV潜伏期的程度。我们以前证明，虽然星形胶质细胞支持HIV感染，但它们限制病毒输出，除非Wnt/b-连环蛋白信号传导途径被破坏（例如，星形胶质细胞中Wnt/B-连环蛋白信号传导的抑制导致生产性HIV复制）。我们提供的初步数据表明，星形胶质细胞分泌特异性Wnt配体（启动Wnt/b-连环蛋白途径的可溶性糖蛋白），以限制HIV在浸润性外周血单核细胞（PBMC）中的复制。我们将定义Wnt配体在白细胞中抑制HIV中的作用，并建立它们这样做的机制。总的来说，这些研究对于提供更好的治疗策略以应对CNS中HIV潜伏期的挑战至关重要。

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.