# GPLD1: Association with Cognition and Amelioration through Exercise in Aging People with HIV

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $789,997

## Abstract

SUMMARY
 This application will study a novel role of the enzyme phosphatidylinositol-glycan-specific phospholipase D
(GPLD1) in relation to physical activity (PA), cognitive outcomes, and relevant mediating pathways, including
inflammation, coagulation, mitochondrial indices and vascular remodeling in aging people with HIV (PWH).
Although PA promotes better cognitive function and quality of life in HIV, PA is problematic for many aging PWH
due to physical limitations from neuropathy, cardiopulmonary disease, and other conditions. Systemic GPLD1
was recently shown to recapitulate the neurogenic and cognitive benefits of exercise and may represent an
alternative approach to gain neural benefits of exercise for those with physical limitations. In an existing cohort
of 100 PWH (50 participating in a PA intervention and 50 controls), we will quantify how GPLD1 levels change
before and after the PA intervention and how these levels associate with plasma markers of inflammation,
clotting, vascular remodeling, mitochondrial indices and neurocognitive (NC) performance. We propose PWH
with higher levels of PA documented by Fitbit and accelerometer monitoring will show greater increases in
GPLD1 than those with lower PA. We hypothesize that higher GPLD1 at baseline will associate with improved
markers of inflammation, abnormal clotting, mitochondrial indices and vascular remodeling and that greater
increases in GPLD1 during the PA intervention will correlate with larger improvements in these indices.
Additionally, we expect that higher baseline GPLD1 will associate with better NC performance and that GPLD1
increases during the 6-month PA intervention will associate with improving NC performance. In addition to human
studies, we will perform translational work to evaluate mechanisms by which GPLD1 exerts salutary effects.
These will include studies in an animal model of virally suppressed PWH on antiretroviral therapy (ART), the
EcoHIV mouse model. In these animals, we will measure the effects of GPLD1 administration on cognition and
markers of inflammation and clotting, including evaluating if the beneficial effects of GPLD1 are blocked by an
inhibitor (phosphatidic acid). In addition, we will characterize inflammation, mitochondrial indices and
synaptodendritic integrity in brain tissue from GPLD1-treated mice. We expect GPLD1 treatment in EcoHIV mice
will improve behavioral performance, reduce brain tissue inflammation and improve synaptodendritic integrity
and mitochondrial indices. In service of future Phase 1 clinical trials, we will examine GPLD1 effects on liver
toxicity in mice. We will also evaluate neuronal cultures for GPLD1 effects on mitochondrial biogenesis and
neurogenesis by exposing cultures to plasma from humans in the PA intervention. We expect PWH plasma with
higher PA will stimulate hippocampal mitochondrial biogenesis and neurogenesis compared to lower PA, and
will determine if serum GPLD1 associates with these outcomes. Examining GPLD...

## Key facts

- **NIH application ID:** 10906758
- **Project number:** 5R01AG074808-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** RONALD J. ELLIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $789,997
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906758

## Citation

> US National Institutes of Health, RePORTER application 10906758, GPLD1: Association with Cognition and Amelioration through Exercise in Aging People with HIV (5R01AG074808-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10906758. Licensed CC0.

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