# Systems Biology of Diffusion Impairment in HIV

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $773,874

## Abstract

ABSTRACT
Mechanisms of impairment of diffusing capacity for carbon monoxide (DLco), which affects over 50 percent of
HIV+ individuals, are poorly understood. No therapies exist despite significant impact on quality of life and
mortality. Identifying molecular pathways of DLco impairment in HIV+ individuals and developing ability to
predict HIV+ individuals at risk of DLco impairment is thus of utmost importance for improving care. In this
proposal, we construct a systems’ modeling approach to identify molecular and clinical pathways contributing
to DLco impairment in HIV+ individuals. We collect multiple parallel molecular datasets integrated with detailed
pulmonary function, radiographic, and echocardiographic measurements to build a comprehensive, systems-
level model of DLco abnormalities in HIV and to develop predictive models of susceptibility to DLco worsening.
As our preliminary data suggest that certain miRNAs, such as the hypoxia-induced and metabolically active
miR-210, may play an important role in DLco abnormalities in HIV, we then perform hypothesis-testing
experiments to determine the impact of miRNAs on lung epithelial and endothelial cells. We utilize our well-
phenotyped cohort of over 500 HIV+ individuals with associated biospecimens to execute the following aims:
Aim 1: To identify key causal molecular pathways of DLco impairment by integrating clinical features and –
omics data from the lung in HIV+ individuals. We will utilize high-throughput RNA sequencing and mass
spectrometry to quantify miRNAs, mRNAs, the microbiome, and metabolites in bronchoalveolar fluid and lung
epithelial cells in HIV+ individuals with detailed pulmonary function, radiographic, and echocardiographic
measurements to construct probabilistic network models of DLco. Key pathways will be validated. Aim 2: To
identify predictive signatures of DLco decline from clinical features, transcriptomic, microbiome, and metabolite
data in easily accessible clinical specimens. We will build predictive models to identify individuals at risk of
developing DLco impairment or having significant decline based on –omics data collected from easily
accessible tissues (miRNA and metabolic profiles from serum and PBMCs; microbiome of the oral cavity),
coupled with detailed clinical and phenotypic data. Aim 3. To investigate the systems-wide relationship
between HIV-induced miRNAs and lung epithelial and endothelial gene reprogramming in HIV+ individuals.
Based on our preliminary data, we will test the hypothesis that PBMCs from HIV+ individuals release miRNAs
that are delivered to lung epithelial and endothelial cells and consequently regulate gene expression, metabolic
function, and activity. These studies investigate an entirely novel paradigm of HIV-mediated communication
with pulmonary cells via extracellular miRNA signaling with direct therapeutic relevance as miRNA levels can
be modulated by augmentation or inhibition of specific miRNAs. This project will leverage existi...

## Key facts

- **NIH application ID:** 10188612
- **Project number:** 5R01HL140963-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** PANAGIOTIS V BENOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $773,874
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188612

## Citation

> US National Institutes of Health, RePORTER application 10188612, Systems Biology of Diffusion Impairment in HIV (5R01HL140963-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10188612. Licensed CC0.

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