# Neutrophil subpopulations and NETosis in HIV-1 pathogenesis

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $222,750

## Abstract

Despite the success of antiretroviral therapy (ART), cardiovascular (CVD), liver (LD), and other chronic
diseases increasingly replace AIDS-related complications as the most common causes of morbidity and
mortality in HIV-1-infected patients. Gut mucosal damage leading to increased intestinal permeability and
ongoing chronic microbial translocation is a central factor in persistent systemic immune activation and
inflammation and represents a critical driving mechanism of HIV-1 pathogenesis. However, the specific
mechanisms and mediators of these processes are not well understood. Neutrophils, the most abundant
immune cell population in the body, are specifically geared for sensitive detection of invading microbial and
viral pathogens and represent the first and most robust innate immune population responding to microbial
translocation. Neutrophil NETosis results in the formation of neutrophil extracellular traps (NETs) that promote
endothelial damage, atherosclerosis, and atherothrombosis. NETs provide the stimulus and the scaffold for
thrombus formation, prime macrophages for the production of cytokines that amplify immune cell recruitment in
atherosclerotic plaques, and induce endothelial damage. We show that neutrophils from HIV-1-infected
patients display a high capacity for NETosis and the production of NETs. The goal of this application is to
identify the specific subpopulations of neutrophils responsible for NETosis in HIV-1-infected individuals. The
central hypothesis of this proposal is that HIV-1 infection is associated with the induction and expansion of
specific neutrophilic subpopulations with increased capacity to undergo NETosis. Reactive oxygen species
(ROS) and NETs released from activated neutrophils promote organ damage and contribute to the progression
of CVD, LD, and other chronic conditions. This hypothesis has been formulated on the basis of our own
preliminary data and recently published reports demonstrating the critical role of neutrophils in HIV-1 infection
and other chronic inflammatory conditions. The overall objective of the proposed studies is to elucidate the
mechanisms responsible for chronic neutrophilic activation and production of NETs in HIV-1 infection in order
to reveal the specific checkpoints for intervention. In preliminary studies, we optimized the methods for detailed
neutrophil characterization and showed that neutrophils from HIV-1-infected individuals display an activated
phenotype, immunosuppressive properties, specific transcriptional profile, increased rate of degranulation, and
a high capacity to undergo NETosis. Using a novel method based on cellular indexing of transcriptomes and
epitopes by sequencing (CITE-Seq), we identified specific neutrophil subpopulations in chronic inflammatory
conditions. Specific properties of the newly identified neutrophil subpopulations strongly indicate that they play
a critical role in the pathogenesis of HIV-1 infection. The objectives of this proposal will be a...

## Key facts

- **NIH application ID:** 10923385
- **Project number:** 1R21AI181662-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Zdenek Hel
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $222,750
- **Award type:** 1
- **Project period:** 2024-07-05 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923385

## Citation

> US National Institutes of Health, RePORTER application 10923385, Neutrophil subpopulations and NETosis in HIV-1 pathogenesis (1R21AI181662-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10923385. Licensed CC0.

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