Interplay between neuroprotective pathways, HIV, and astrocytes

艾滋病毒会导致神经疾病(神经艾滋病)，范围从轻微的认知和运动障碍到艾滋病毒- 伴发痴呆(HAD)。需要更好地了解神经艾滋病的潜在机制 因为这将为治疗神经艾滋病提供建议。为了实现这个目标，我们的战略是明确 脑细胞内源性神经保护机制与HIV的相互作用。WNT/？-连环蛋白活性 是神经元和星形胶质细胞中支持生存的信号。Wnt/β-catenin调控多种细胞中的~500个基因 细胞的增殖和存活等功能遍及全身，包括中枢神经系统。越来越多的证据 链接降低了-连环蛋白和神经退行性变的水平。然而，Wnt/？-catenin活性在 神经艾滋病尚不清楚。我们报告了Wnt/？-catenin活性与HIV复制之间的负相关关系。 具体地说，我们证明了活性的Wnt/？-catenin抑制而非活性的Wnt/？-catenin诱导HIV 复制。此外，干扰素，一种与HAD严重程度相关的促炎细胞因子，以及TAT，一种HIV编码的 调节蛋白，两者都减弱了星形胶质细胞中的Wnt/？-catenin信号。我们提出(I)Wnt/？-catenin 信号(Wnt)是HIV复制和大脑内稳态的关键调节因子，以及(Ii)Wnt下调 (由TAT或干扰素介导)促进星形胶质细胞和神经元的凋亡，这在发病机制中起作用。 在中枢神经系统的艾滋病毒疾病。在目标1中，使用星形胶质细胞(具有高内源性Wnt/β-catenin表达) 我们将定义Wnt/？-catenin调控HIV复制的机制。在目标2中，使用星形胶质细胞， 小胶质细胞和单核细胞来源的巨噬细胞，我们将确定宿主(干扰素)和病毒(TAT)因素的作用 在调节Wnt/？-catenin信号和HIV复制方面。在目标3中，使用原代人类胎儿混合 神经胶质/神经元细胞培养，我们将确定大脑Wnt活动调节的后果 星形胶质细胞和神经元的存活。总而言之，这些研究将使我们更好地理解 大脑Wnt/？-catenin活性对HIV复制和神经胶质细胞/神经元存活的影响。这些研究也可以加快 -连环蛋白信号激活剂的发展可以穿透中枢神经系统，抑制艾滋病毒复制，以及 提高星形胶质细胞和神经元的存活率。

HIV causes neurologic disorders (NeuroAIDS) ranging from minor cognitive and motor disorders to HIV- associated dementia (HAD). A better understanding of the underlying mechanisms of NeuroAIDS is needed because it would suggest therapeutic approaches for NeuroAIDS. Towards this goal, our strategy is to define the interplay between endogenous neuroprotective mechanisms and HIV in brain cells. Wnt/¿-catenin activity is a pro-survival signal in neurons and astrocytes. Wnt/¿-catenin regulates ~500 genes involved in diverse cell functions such as cell proliferation and survival throughout the body, including the CNS. Mounting evidence links decreased levels of ¿-catenin and neurodegeneration. Yet, the role of Wnt/¿-catenin activity in NeuroAIDS is unclear. We reported an inverse relationship between Wnt/¿-catenin activity and HIV replication. Specifically, we demonstrated that active Wnt/¿-catenin inhibits whereas inactive Wnt/¿-catenin induces HIV replication. Further, IFN¿, a proinflammatory cytokine associated with HAD severity, and Tat, an HIV-encoded regulatory protein, both diminished Wnt/¿-catenin signaling in astrocytes. We propose that (i) Wnt/¿-catenin signaling (Wnt) is a key regulator of HIV replication and homeostasis in the brain, and (ii) Wnt down-regulation (mediated by Tat or IFN¿) promotes astrocyte and neuronal apoptosis, which contributes to the pathogenesis of HIV disease in the CNS. In Aim 1, using astrocytes (which have high endogenous Wnt/¿-catenin expression) we will define the mechanism by which Wnt/¿-catenin regulates HIV replication. In Aim 2, using astrocytes, microglia, and monocyte-derived macrophages, we will determine the role of host (IFN¿) and viral (Tat) factors in modulating Wnt/¿-catenin signaling and HIV replication. In Aim 3, using primary human fetal mixed glial/neuronal brain cell cultures, we will determine the consequences of modulation of brain Wnt activity on the survival of astrocytes and neurons. Collectively, these studies will lead to a better understanding of the role of brain Wnt/¿-catenin activity on HIV replication and glial/neuronal survival. These studies could also expedite the development of activators of ¿-catenin signaling that can penetrate the CNS, suppress HIV replication, and enhance survival of astrocytes and neurons.