# Mechanisms of defective mitophagy and cellular senescence in HIV associated COPD

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2020 · $469,229

## Abstract

PROJECT SUMMARY
 In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality.
Lung diseases such as bacterial pneumonia, COPD and pulmonary hypertension are emerging as significant
comorbidities in the people living with HIV. COPD continues to be an important comorbidity in HIV- infected
patients even though anti-retroviral therapy has succeeded in restoring CD4 cell counts and decreasing
infections by pneumocystis. HIV is an independent risk factor for COPD even when compensated for smoking
status. Senescence associated proinflammatory cytokines play and important role in the chronic inflammation
which is a hallmark of COPD. Impaired mitophagy leads to accumulation of depolarized defective mitochondria
that demonstrates increased ROS production and release of Damage associated Molecular patterns (DAMPs)
with a concomitant increase in senescence associated secretory phenotype (SASP) associated cytokines.
 Cigarette smoking is the primary means of nicotine addiction in people living with HIV. The pharmacologic
effects of nicotine-mediated release of dopamine, glutamate and GABA cause nicotine dependence. A
disproportionately high number of HIV infected people are addicted to nicotine and smoke tobacco compared
to the general population in the United States. We show that HIV Tat and cigarette smoke mediate some of
their effects via a common pathway involving TGF-β signaling. Tat and TGF-β alter the microRNAome of
bronchial epithelial cells leading to suppression of some of the key genes involved in mitophagy and general
macroautophagy. Taken together with our reports that HIV Tat and Cigarette smoke increase lung
inflammation, this suggests that the altered microRNAome may manifest as the initiating event in HIV and CS
associated COPD with increased severity of onset observed in HIV smokers. Hence neutralizing HIV tat and
modulating TGF-β signaling in the airway can arrest or even reverse lung “inflammaging” thereby preventing or
slowing down the onset of clinical disease.
 Based on these observations, Aim 1 will determine the role of miRNAs involved in HIV Tat and cigarette
smoke associated impaired mitophagy. Aim 2 will relate altered mitophagy and consequent senescence with
increased secretion in SASP associated cytokines and DAMPs in primary small airway epithelial cells (SAECs)
in vitro and in small animal lung-specific Tat transgenic models and donor lungs from HIV
smokers/nonsmokers. Aim 3 will determine therapeutic approaches to rescue the effects of Tat and TGF-β to
rescue mitophagy and consequently inhibit stress induced senescence and aberrant SASP cytokines and
DAMPs. The proposal aims will address one of the major high priority areas identified for HIV research
namely comorbidities in people living with HIV and substance abuse.

## Key facts

- **NIH application ID:** 9978609
- **Project number:** 5R01HL147715-02
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** HOSHANG JEHANGIR UNWALLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,229
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978609

## Citation

> US National Institutes of Health, RePORTER application 9978609, Mechanisms of defective mitophagy and cellular senescence in HIV associated COPD (5R01HL147715-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978609. Licensed CC0.

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