HIV latency in astrocytes

描述（由申请人提供）：HIV在急性感染期间侵入中枢神经系统，并在联合抗逆转录病毒治疗后持续存在于大脑中。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，星形胶质细胞（占脑细胞的50-70%）是HIV的储存库，表现出定义HIV储存库的几个重要特征。然而，人们对星形胶质细胞中HIV潜伏的分子机制和星形胶质细胞中HIV区隔的程度知之甚少。为了解决这些知识空白，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CD4+ T细胞所参与的修饰有何不同或相似之处。此外，尽管有大量研究记录了HIV在中枢神经系统中的区隔化，但很少有证据表明星形胶质细胞中HIV区隔化的程度及其与HAND严重程度的关联。我们将评估星形胶质细胞中HIV区隔化的程度及其与巨噬细胞/小胶质细胞中HIV的关系，以及与不同程度HAND的相关性。最后，我们将更好地定义星形胶质细胞在神经艾滋病中的新的双重作用，它可能调节HIV在中枢神经系统中的潜伏期。我们之前证明，虽然星形胶质细胞支持HIV感染，但它们限制病毒的输出，除非Wnt/b-catenin信号通路被破坏（例如，星形胶质细胞中抑制Wnt/b-catenin信号通路导致HIV多产复制）。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-catenin途径的可溶性糖蛋白）来限制HIV在浸润外周血单核细胞（PBMCs）中的复制。我们将定义Wnt配体在白细胞中抑制HIV的作用，并建立其机制。总的来说，这些研究对于提供更好的治疗策略来应对艾滋病毒在中枢神经系统中的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.