# Targeting the Cholinergic Pathway in HIV-associated Inflammation and Cognitive Dysfunction

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $741,975

## Abstract

PROJECT SUMMARY
Although anti-retroviral therapy (ART) enhances life expectancy and overall quality of life (QoL), HIV-infected
individuals are increasingly vulnerable to non-AIDS-related diseases including HIV-associated neurocognitive
disorders (HAND)
.
Inflammation, particularly activated monocytes/macrophages (M/M), is considered to be a
primary mechanism in the pathogenesis of HAND. Tobacco use may further exacerbate inflammation and thus
increase the incidence and severity of HAND. Conversely, nicotine alone has anti-inflammatory effects, mainly
through activation of the α7 nicotinic receptors (nAChRs) suggesting that stimulating the cholinergic pathway
may be a novel therapeutic target to suppress inflammation and reverse or prevent neurocognitive deficits in
HIV-1 infection. Consistent with RFA-DA-17-020, this proposal seeks to evaluate a pharmacological treatment
that targets cholinergic function, improves neurocognition, and attenuates inflammation, to probe the
interaction between inflammation, nicotinic receptors and smoking in HIV-infected people, and potentially
mitigate HIV-associated adverse health consequences, including HAND. We will utilize galantamine (GAL), an
FDA-approved procognitive medication that increases endogenous levels of acetylcholine by inhibiting the
acetylcholinesterase enzyme and acting as a positive allosteric modulator of the α7 nAChRs. Based on
evidence that inflammation is implicated in the pathogenesis of HAND, and that GAL has anti-inflammatory
properties, we hypothesize that: (1) nAChR modulation by GAL will reduce chronic residual inflammation and
improve neurocognition in ART-treated HIV infection; and (2) that these effects will be larger among chronic
smokers (vs. nonsmokers) due to the synergistic effects of nicotine and GAL. In this double-blind, placebo-
controlled crossover study, HIV-infected individuals (N=120; 60 smokers, 60 nonsmokers) will be randomized
to 12 weeks of GAL or placebo, followed by a 4-week washout, then 12 weeks of GAL or placebo (arms
switched). All subjects will be stable on ART and the GAL dose will follow FDA guidelines. At the beginning
and end of each treatment phase, M/M and T cell activation markers, soluble inflammatory biomarkers, and
viral load will be assessed. Monocyte transcriptomics will also be assessed on a subset of the sample (n=60;
30/group). Neurocognition and clinical outcomes (e.g., chronic fatigue, QoL) will be measured at baseline and
at 4-week intervals during each treatment phase. The primary outcomes are M/M and T cell activation (CD16,
CD163, and CCR2 expression; plasma CCL2 [MCP-1] and sCD14; CD38/HLA-DR on CD8 cells) and
neurocognitive performance (processing speed, verbal learning/memory, executive function). Exploratory
outcomes include monocyte gene expression patterns and broad plasma cytokine analysis. This innovative
approach will provide mechanistic insight into the interactions among nAChR activation, HIV immune activation
and pathogenesi...

## Key facts

- **NIH application ID:** 9962340
- **Project number:** 5R01DA044906-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rebecca Ashare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $741,975
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962340

## Citation

> US National Institutes of Health, RePORTER application 9962340, Targeting the Cholinergic Pathway in HIV-associated Inflammation and Cognitive Dysfunction (5R01DA044906-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9962340. Licensed CC0.

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