HIV induces AQP4 dysfunction and aberrant waste clearance from brain leading to worsening HAND

项目总结： 淋巴清扫系统促进间质液和脑脊液的交换 通过动脉血管周围间隙进入大脑。这一过程部分由水通道蛋白-4(AQP4)促进。 水通道主要位于星形胶质细胞末端的足部，毗邻血脑屏障的内皮细胞。 AQP4表达水平的改变或从星形细胞末端脚到胞体的错误定位可导致 ISF流量的减少导致细胞外废物的堆积，如过度磷酸化的牛磺酸(PTAU)。 Ptau积聚是阿尔茨海默病(AD)的神经病理特征，在一些患有 人类免疫缺陷病毒(HIV)。大约50%的艾滋病毒携带者(PWH)患有艾滋病毒- 相关神经认知障碍(手)，这是一种与认知和运动有关的谱系障碍 PWH下降。有限的研究表明，在HIV CNS感染中，脑内AQP4的表达水平 有症状手的PWH患者额中回的匀浆显著增加。 与那些没有症状的手相比，这提出了一个问题，即AQP4功能和亚细胞 本土化可能会影响认知状态。此外，常见的单核苷酸多态(SNPs)在 在一些神经退行性疾病中，aqp4基因与认知能力下降的速度更快有关。 因此，有可能aqp4的常见突变、亚细胞定位错误、功能障碍、表达 水平或翻译后修饰对Hand有贡献。其他神经炎症性疾病的研究 已发现AQP4通过腺苷A2aR(A2aR)信号调节失调。A2aR激活导致 PKC介导的AQP4(Ser180，Ser276)抑制磷酸化被认为与通道有关 内化、错位和表达减少。我的总体假设是，在威斯康星医院， AQP4可能部分通过减少有毒异常蛋白和艾滋病毒的清除而对HAND起作用 AQP4的机械性改变部分是通过A2aR的失调实现的。为了检验这一假设，我们提出了三个 明确的目标。目的1：确定慢性阻塞性肺疾病脑组织中AQP4及其相关通路是否发生改变 与CI状态以及PTAU和A累积相关。我们假设AQP4水平和定位 在有更严重脑梗塞死亡和ptau证据的HIV患者中，A2aR信号被干扰 积累。目的2：确定aqp4 SNPs是否与PWH患者CI状态的改变相关。联谊会 PLWH中不同CI水平的aqp4常见SNP的分布。我们假设HIV改变了AQP4的功能 并通过PKC介导的AQP4(Ser180，Ser276)+/-CART的抑制磷酸化进行定位。目标3： 确定HIV如何改变体外培养的星形胶质细胞中AQP4的功能。我们假设HIV改变了AQP4 蛋白激酶C通过抑制AQP4(Ser180，Ser276)+/-CART的磷酸化实现其功能和定位。 这些研究的数据可能会导致发现艾滋病毒和抗逆转录病毒治疗的新机制 在老化的PWH中，AQP4功能受损。

Project Summary: The glymphatic fluid clearance system promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid through the arterial perivascular spaces into the brain. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocyte end feet abutting endothelial cells of the blood brain barrier. Changes in expression levels or mislocalization of AQP4 from astrocytic end feet to the soma can lead to decreased ISF flow leading to buildup of extracellular waste products like hyperphosphorylated Tau (pTau). pTau accumulation is a neuropathological hallmark in Alzheimer's disease (AD) and in some people with human immunodeficiency virus (HIV). Approximately 50% of people with HIV (PWH) suffer from HIV- associated neurocognitive disorders (HAND), which is a spectrum disorder linked to cognitive and motor decline in PWH. Limited studies have shown that in HIV CNS infection expression levels of AQP4 in brain homogenates from the mid-frontal gyrus of PWH with symptomatic HAND were significantly increased compared to those with asymptomatic HAND, which raises the question if AQP4 function and subcellular localization may contribute to cognitive status. In addition, common single nucleotide polymorphisms (SNPs) in the aqp4 gene have been associated with more rapid cognitive decline in some neurodegenerative diseases. Therefore, it is possible that common mutations in aqp4, subcellular mislocalization, dysfunction, expression levels or post-translational modifications contribute to HAND. Studies in other neuroinflammatory diseases have shown dysregulation of AQP4 through the adenosine A2aR (A2aR) signaling. A2aR activation leads to PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) that is proposed to contribute to channel internalization, mislocalization and decreased expression. My overall hypothesis is that in PWH, changes in AQP4 may contribute, in part, to HAND by decreasing clearance of toxic aberrant proteins and HIV mechanistically alters AQP4 in part via dysregulation of A2aR. To test this hypothesis, we proposed three specific aims. Aim 1: Determine if AQP4 and associated pathways are altered in brain tissues from PWH and associates with CI status and pTau and Aaccumulation. We hypothesize that AQP4 levels and localization and A2aR signaling are disrupted in HIV patients with more severe CI at death and evidence of pTau accumulation. Aim 2: Determine if aqp4 SNPs are associated with changes in CI status in PWH. Association of common SNPs in aqp4 with different levels of CI in PLWH. We hypothesize that HIV alters AQP4 function and localization via PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) +/- cART. Aim 3: Determine how HIV alters AQP4 functioning in astrocytes in vitro. We hypothesize that HIV alters AQP4 function and localization via PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) +/- cART. Data from these studies may lead to the discovery of new mechanisms by which HIV and anti-retroviral therapy contribute to impaired AQP4 functioning in aging PWH.