# Enhancing mitochondrial metabolism to rescue Immune dysfunction in immune non responders to ART

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $207,302

## Abstract

The introduction of combination antiretroviral therapy (ART) has had major impact on morbidity
and mortality of HIV-1 infected persons. Nonetheless, despite effective control of HIV replication
with ART, a minority of treated persons fails to increase CD4+T cell counts to levels observed in
uninfected subjects 1,2. These immune failure or immune non-responder (INR) subjects remain at
greater risk for morbidity and mortality than are immune responders (IR) in whom CD4+T cell
count is restored 3,4. Despite low CD4+T cell numbers, increased frequency of cycling CD4+T-
cells is a hallmark of poor immune reconstitution in these persons1,2. In addition, high levels of
inflammation are characteristic 1,5,6 and an exhaustion/senescence phenotype of CD4+T cells has
been reported 5,6. Importantly, the INR phenotype is more common in older individuals 7,8.
Based on our preliminary data, we hypothesize that mitochondrial dysfunction underlies the
INR phenotype. We proposed a model where INR subjects fail to restore CD4+T cells as a
consequence of defective mitochondrial fitness that affects negatively Treg survival and function.
This leads to uncontrolled cell cycling, immune exhaustion, and increased cell death.
The working hypothesis of this proposal in based on our preliminary data that will appear soon in
the Journal of Clinical Investigation (Ref. 37). First, we showed that in all persons, cycling CD4+T
cells are enriched for cells having a phenotype of regulatory T cells (Tregs). Second, sorted
cycling CD4+T cells of INRs do not complete cell cycle or proliferate in vitro in contrast to findings
among IR or healthy controls that do. Third, we found cycling Tregs of INR were dysfunctional by
transcriptomic and flow cytometry analyses and this was linked to low CD4+T cell counts and to
impaired mitochondrial activity. Fourth, we showed that exposure of cycling CD4+T cells and
Tregs from INR to IL-15 corrects mitochondrial dysfunction and improves T cell proliferation by
induction of the master regulator of mitochondrial biogenesis, the peroxisome proliferator-
activated receptor gamma coactivator 1-alpha (PGC1). Thus, we hypothesize that enhancing
mitochondrial biogenesis might correct exhaustion and senescence that are
characteristics of CD4+ T cells in INRs. PGC1 can be induced through at least three distinct
pathways: 1) activation of the peroxisome proliferator-activated receptors (PPAR, PPAR,
PPAR) nuclear transcription factors regulating genes implicated in mitochondrial biogenesis and
bioenergy9,10, 2) activation of AMP-activated protein kinase (AMPK) by agents such as
Resveratrol and the AMP analog, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR ) or
3) activation of the mammalian target of rapamycin (mTOR) (See Figure 2). We hypothesize that
mitochondrial dysfunction drives immune failure in INRs as a consequence of diminished
PGC1 expression that is correctible through exposure to IL-15 and/or combinations of
PGC1 inducers (PPAR/AM...

## Key facts

- **NIH application ID:** 10316832
- **Project number:** 7R21AG062386-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Souheil Antoine Younes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $207,302
- **Award type:** 7
- **Project period:** 2019-04-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316832

## Citation

> US National Institutes of Health, RePORTER application 10316832, Enhancing mitochondrial metabolism to rescue Immune dysfunction in immune non responders to ART (7R21AG062386-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10316832. Licensed CC0.

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