# PREVENTING ALZHEIMER’S DISEASE-LIKE BRAIN PATHOLOGY IN HIV INFECTION BY TARGETING CCR5

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $690,748

## Abstract

PROJECT ABSTRACT
Brain tissues from people living with HIV (PLWH) showed evidence of Alzheimer’s Disease (AD)-like pathologies,
including increased neurotoxic amyloid-b (Ab40/42), amyloid plaques and Tau hyperphosphorylation (pTau)
associated with neurodegeneration and HIV-associated neurocognitive disorders (HAND). The mechanisms
through which HIV increase Ab, pTau, and induce AD-like central nervous system (CNS) impairment are not
known. Although most PLWH with CNS Ab plaques and pTau had been on long-term antiretroviral therapy (ART),
the role of ART in pTau and Ab production, and AD-like pathologies has not been investigated. Findings from
our R21 studies, using in vitro, in vivo and ex vivo approaches, demonstrated that HIV-1 significantly increased
CNS Ab42 and pTau in humanized mice, and this was associated with significantly 1) increased expression and
activation/activity of b-secretase-1 (BACE1), soluble (s)APPb (amyloidogenic pathway effectors), and GSK3b
(kinase that phosphorylates Tau); 2) reduced expression/activity of neprilysin (NEP, Ab-degrading enzyme); 3)
increased blood-brain barrier (BBB) expression of the receptor for advanced glycation end products (RAGE,
mediates Ab CNS influx), and reduced BBB expression of low-density lipoprotein receptor–related protein-1
(LRP1, mediates CNS Ab efflux); and 4) increased neuroinflammation, neuronal damage and BBB injury. We
demonstrated that LRP1 and CCR5 mediated Ab transport through the BBB, that AZT potentiated HIV-induced
upregulation/activation of BACE1, sAPPb and GSK3b, and that AZT blocked NEP expression/activity.
Significantly, the CCR5 antagonist maraviroc (MVC) abrogated these HIV- and AZT- induced effects.
Thus, we hypothesize that CCR5, via LRP1, plays a major role in Ab formation, transport, and catabolism,
amyloidogenesis and pTau in PLWH, and that targeting CCR5 prevents HIV-induced Ab and pTau,
increases Ab CNS efflux, and abrogates CNS injury and HAND. Using a validated HIV/AIDS animal model,
primary human cells and human brain tissues, we will test this hypothesis and further investigate the effects of
commonly prescribed antiretroviral (ARV) drugs (AZT, TDF) on HIV-induced activation of BACE1 and APP
amyloidogenic pathway, Tau metabolism, and CNS injury (Aim-1); Ab transport, degradation, clearance, and
neuroinflammation (Aim-2); and associated BBB transcriptomic and epigenomic signatures (Aim-3). These
mechanistic studies will help determine whether HIV induces amyloidogenesis by i) activating BACE1 pathways
to increase Ab production or ii) by interfering with LRP1-mediated Ab transport, degradation, clearance; iii) the
role of ARVs; iv) whether CCR5 modulates these effects; and v) characterize the brain vascular transcriptome
and epigenome associated with HIV/ARVs-induced dysregulation and MVC protective effects. Our proposed
studies are of high-impact, translational significance, and address the NIH high priority research areas that focus
on “Examining the pathophysi...

## Key facts

- **NIH application ID:** 10821386
- **Project number:** 5R01MH132517-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** GEORGETTE D. KANMOGNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $690,748
- **Award type:** 5
- **Project period:** 2023-04-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821386

## Citation

> US National Institutes of Health, RePORTER application 10821386, PREVENTING ALZHEIMER’S DISEASE-LIKE BRAIN PATHOLOGY IN HIV INFECTION BY TARGETING CCR5 (5R01MH132517-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10821386. Licensed CC0.

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