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

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $435,875

## Abstract

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 discove...

## Key facts

- **NIH application ID:** 10619083
- **Project number:** 1R21NS131101-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Dianne Teresa LANGFORD
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $435,875
- **Award type:** 1
- **Project period:** 2022-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10619083

## Citation

> US National Institutes of Health, RePORTER application 10619083, HIV induces AQP4 dysfunction and aberrant waste clearance from brain leading to worsening HAND (1R21NS131101-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10619083. Licensed CC0.

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