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

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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.