# A CRISP(e)R approach to alleviating HIV-associated COPD

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2024 · $472,980

## Abstract

PROJECT SUMMARY
People living with HIV demonstrate increased incidence of lung inflammation and HIV is an independent risk
factor development of COPD. In the era of antiretroviral therapy (ART) with markedly improved life expectancy,
lung related chronic conditions like COPD and bacterial pneumonia are primarily responsible for increased
morbidity and mortality in people living with HIV (PLWH). HIV patients die of non-AIDS comorbidities almost a
decade earlier that their non-HIV counterparts. Identifying the pathophysiological mechanism and treatment of
HIV-associated comorbidities is very complex in chronic lung diseases, even with ART. TGF-β signaling
upregulated by HIV Tat, and Tat itself alters the microRNAome of the airway epithelium. MicroRNAs play
important roles in lung health and diseases and their dysregulation can serve as pathological hallmarks of several
lung diseases. TGF-β signaling, plays a vital role in the progression of chronic airway diseases like COPD and
lung infections. This is important since we have shown that TGF-β can increase the viral burden in the airway
thereby establishing a positive feedback loop mechanism. HIV Tat and TGF-β1 upregulates miR-126-3p, a
microRNA known to suppress IRS-1 which leads to upregulation of ADAM17 in airway epithelial cells which
leads to impaired mitophagy, senescence and lung inflammation in vitro and in vivo.
The current proposal focuses on determining the pathophysiological mechanism and rescue by which HIV-
associated COPD through TGF-β alter the microRNAome to mediate suppression of critical genes in mitophagy
leading to defective mitophagy, senescence and inflammation. Aim 1 will identify a novel crosstalk between the
defective microRNAome, IRS-1 and ADAM17 with downstream effects on mitochondrial homeostasis,
senescence, and inflammation in the context of HIV and CS. We will validate this pathway using miRNA mimics
and antagomiRs in vitro and in vivo on lung inflammation in air and CS-exposed SP-C Tat transgenic. Aim 2 will
test therapeutic approaches given that miRNA target sites differ among different genes regulated by the same
miRNA, editing the miR-126-3p target site on IRS-1 3’ UTR will preserve IRS-1 levels in the context of HIV and
CS thereby restoring baseline mitophagy, senescence and mitigating inflammation in EcoHIV mouse models of
HIV infection.

## Key facts

- **NIH application ID:** 11006004
- **Project number:** 1R01HL176254-01
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Srinivasan Chinnapaiyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $472,980
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006004

## Citation

> US National Institutes of Health, RePORTER application 11006004, A CRISP(e)R approach to alleviating HIV-associated COPD (1R01HL176254-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11006004. Licensed CC0.

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