# Effect of ILC3 loss on epithelial barrier function during ART Treated HIV infection

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2024 · $234,000

## Abstract

Project Summary:
Our project aims to investigate the mechanisms behind the loss of Type 3 innate lymphoid cells (ILC3) in
antiretroviral therapy (ART) treated People Living with HIV (PLWH) and the subsequent impact on intestinal
epithelial barrier integrity. Chronic immune activation is a hallmark of HIV infection that persists in PLWH on ART
and is linked to non-infectious comorbidities. Microbial translocation (MT) due to decreased mucosal barrier
integrity is in part responsible for driving HIV-associated inflammation. Therefore, it is critical to understand
mechanisms underlying barrier integrity in ART treated PLWH. ILC3s are essential for the maintenance of the
gut epithelial barrier and are depleted during early HIV infection and are not restored with ART. Decreased
frequency of these cells during HIV infection likely contributes to decreased epithelial barrier integrity leading to
increased MT. Since ILC3s are not susceptible to direct HIV infection and a viable model to study their loss has
yet to be developed, the mechanism behind their loss remains poorly understood. To address this gap in
knowledge, we will use human intestinal explants as a model system to study early HIV infection. These explant
tissues contain ILC3s, epithelial cells, and other immune cells that are susceptible to HIV infection. Our
preliminary data show that these explant tissues remain viable for up to 7 days, can harbor HIV infection and
ILC3s are depleted following HIV infection, providing this as a viable model to study HIV-associated ILC3
depletion. Furthermore, we and others have shown that ILC3s respond to specific bacteria found in the gut
microbiome. This is emphasized as PLWH have a distinct enteric microbiome that is not reverted with ART. To
fully model the intestinal environment during HIV infection, and the subsequent impact on ILC3 function, we will
introduce an HIV-associated microbiome to the intestinal explant tissues. Ultimately, using these explants with
HIV infection and HIV-associated microbiomes will shed light on the underlying mechanisms behind the loss of
ILC3s and the effect on intestinal epithelial barrier integrity. This understanding could lead to the development
of new therapeutic approaches to improve barrier integrity and reduce HIV-associated inflammation and
comorbidities in PLWH.

## Key facts

- **NIH application ID:** 10923303
- **Project number:** 1R21DK138855-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Charles Preston Neff
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2024-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923303

## Citation

> US National Institutes of Health, RePORTER application 10923303, Effect of ILC3 loss on epithelial barrier function during ART Treated HIV infection (1R21DK138855-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10923303. Licensed CC0.

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