# Astoglial reactivity and metabolism in aging people with HIV

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $316,000

## Abstract

SUMMARY
 Over 37 million people worldwide are infected with HIV and as many as 50% are affected by some form of
neurological dysfunction. Despite effective antiretroviral therapy (ART) extending the lifespans of people with
HIV (PWH), treatments to reduce the prevalence of HIV-associated neurocognitive disorder (HAND) and other
age-related diseases are lacking. Increased mitochondrial activity in reactive astroglia play a causal role in
mitochondrial dysfunction in neurons and this may be a targetable mechanism underlying neuronal dysfunction
in virally suppressed PWH, particularly in aging populations. Indeed, there is evidence that aging PWH may be
susceptible to age-related diseases such as Alzheimer’s disease (AD). Early during HIV infection, HIV-infected
monocytes enter the brain and spread infection to resident microglia that then release HIV, HIV proteins, and
inflammatory cytokines, which stimulate a proinflammatory phenotype in astroglia. Reactive astroglia are a
hallmark of postmortem brain tissues from HAND and AD. Astroglia have many homeostatic functions, which
are likely disrupted by chronic low-level HIV infection, long-term exposure to ART and the age- and AD-related
protein beta amyloid (Ab). One important function of astroglia is to buffer the concentrations of metabolic
substrates (glucose, lactate, and glutamine) available to neurons in the extracellular space. Despite this crucial
function to maintain bioenergetic homeostasis in the brain and the well-documented evidence of bioenergetic
deficits during HAND and AD, little is known about how these processes are affected in reactive astroglia. We’ve
recently discovered that HIV and ART stimulate a switch in astroglia from being primarily glycolytic and secreting
the byproduct lactate, to relying on oxidative phosphorylation to meet energy demands. To achieve this increase
in mitochondrial activity, reactive astroglia increase levels of the mitochondrial biogenesis factor TFAM, which is
associated with a reduction in TFAM expression and viability in neurons. Importantly, this neurotoxicity is blocked
by anti-inflammatory compounds that inhibit mitochondrial activity and reduce the inflammatory phenotype of
astroglia. However, the mechanistic link between increased mitochondrial activity in reactive astroglia and the
reduction in mitochondrial biogenesis in neurons is not understood. We will investigate the role of astroglial
metabolism in aging PWH by testing the hypothesis that the age-related protein Aβ synergizes with HIV,
ART and inflammatory cytokines in an age- and TFAM-dependent manner to induce reactive astroglia.
SA1 will test in human astrocyte cultures from young and aged donors how TFAM knockdown alters
mitochondrial activity and inflammatory gene expression in reactive astroglia. SA2 will investigate in postmortem
brain tissues from HIV-, HIV- with AD, and in PWH with and without HAND changes in astroglial TFAM and the
relationship with Ab plaques. These AIMs addres...

## Key facts

- **NIH application ID:** 10846438
- **Project number:** 3R01MH128108-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jerel Adam Fields
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $316,000
- **Award type:** 3
- **Project period:** 2022-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846438

## Citation

> US National Institutes of Health, RePORTER application 10846438, Astoglial reactivity and metabolism in aging people with HIV (3R01MH128108-02S1). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10846438. Licensed CC0.

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