# HIV infection-induced mitochondrial dysfunction and premature T cell aging

> **NIH NIH R15** · EAST TENNESSEE STATE UNIVERSITY · 2021 · $427,618

## Abstract

HIV infection-induced mitochondrial dysfunction and premature T cell aging
HIV infection appears to drive premature T cell aging, evidenced by mitochondrial dysfunction. How CD4 T cells
develop mitochondrial dysfunction during HIV infections is unclear. The objective of this proposal is to elucidate the
mechanisms of mitochondrial dysfunction during chronic HIV infection, so as to develop effective means to rescue
CD4 T cell depletion or functional impairment, the sine que non of HIV-infection. To elucidate the mechanisms
underlying mitochondrial dysfunction in CD4 T cell aging, we analyzed the mitochondrial function of CD4 T cells
derived from ART-controlled HIV patients. Our preliminary data show that HIV CD4 T cells have decreased
mitochondrial DNA (mtDNA) content, mitochondrial respiration, and ATP production. To identify candidate proteins
involved in dysregulating mtDNA copy numbers, we performed Liquid Chromatography Mass Spectrometry (LC-MS)
on purified mitochondria from CD4 T cells of HIV patients and health subjects (HS). We found largest reduction of
mitochondrial proteins (SOD1 and PRDX1) in destroying reactive oxygen species (ROS), and in repair of ROS-
mediated DNA damage repair (APEX1), and elevation of proteins in mtDNA degrading (EXOG and ENDOG) and
mtDNA replication (POLG and MGME1). Based on these and other preliminary data, we hypothesize that ROS-
mediated mtDNA damage (via lower SOD1 and/or PDRX1 and APEX1) may cause higher mtDNA degradation (by
EXOG and ENDOG), which may not be sufficiently complemented by mtDNA replication (through higher POLG and
MGME1), leading to lower mtDNA copy number and impaired mitochondrial functions that we have seen in HIV-
derived CD4 T cells. We propose two aims to define the mechanisms leading to mtDNA decrease and compromised
function. In Aim 1, We will determine if ectopic expression of SOD1 and/or PRDX1 can reduce ROS level and
oxidative mtDNA damage in CD4 T cells of HIV patients. In addition, ectopic expression of APEX1 will be performed
to determine the involvement of APEX1 in repairing damaged mtDNA via the base excision repair (BER) pathway.
siRNA knockdown of SOD1 and/or PRDX1, and APEX1 will also be performed in healthy CD4 T cells to confirm
their roles in mtDNA damage and copy number maintenance, mitochondrial respiration, and ATP production. In Aim
2, we will use transient siRNA knockdown or Crisper/Cas9 knockout to reduce the EXOG and/or ENDOG nucleases
in CD4 T cells from HIV patients, and to assess the levels of oxidative mtDNA damage and rescue of mtDNA copy
number. We will perform single molecule analysis of replicated DNA (SMARD) on mtDNA in cultured CD4 T cells
from HIV patients to comprehensively assess the status of mtDNA replication in response to T cell receptor (TCR)
stimulation. Overall, this application is novel and strong in both concept and approach to answer clinically relevant
questions: how chronic viral infection induces mitochondrial dysfunction, leading to p...

## Key facts

- **NIH application ID:** 10203459
- **Project number:** 1R15AG069544-01A1
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** Zhi Q. Yao
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,618
- **Award type:** 1
- **Project period:** 2021-09-05 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10203459

## Citation

> US National Institutes of Health, RePORTER application 10203459, HIV infection-induced mitochondrial dysfunction and premature T cell aging (1R15AG069544-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10203459. Licensed CC0.

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