# Molecular mechanisms underlying HIV related intestinal epithelial barrier dysfunction

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $748,281

## Abstract

Abstract
The goal of proposed experiments in this application is to determine how HIV infection disrupts intestinal
barrier function. It is now appreciated that microbial translocation across an impaired epithelial barrier leads to
circulating LPS, persistent immune activation and chronic inflammation in people living with HIV (PLWH).
These HIV associated effects are important contributors to premature development of neurocognitive
disorders, cardiovascular disease, metabolic syndrome and bone abnormalities even in PLWH on optimal
combination antiretroviral therapy (cART). Untreated infection is characterized by the production of
proinflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNFα). Following
therapy, cytokine levels decline but chronic inflammation continues. Prevention of inflammation-induced
comorbidities requires the development of more specific therapeutics targeting the underlying cause. However,
a gap exists in our understanding of the underlying molecular pathways involved. This proposal will capitalize
on an established collaboration between investigators with expertise in HIV biology and intestinal barrier
function/pathobiology. We have generated strong preliminary data that provides a framework for understanding
the underlying link between disrupted intestinal epithelial barrier function and HIV infection. While the overall
chronic inflammatory manifestations of HIV infection are likely to be multi-factorial, our exciting results support
an overarching hypothesis that lamina propria HIV-1 infected primary human CD4+T lymphocytes that closely
interact with intestinal epithelial initiate a process leading to enhanced production of pro-inflammatory
cytokines that negatively impact epithelial homeostasis resulting in a leaky intestinal barrier. Given these
important new insights, funding is requested to support a major collaborative effort between established
investigators in the areas of HIV biology and intestinal inflammation/barrier disruption to determine the
mechanism(s) through which primary human intestinal epithelial cells (IECs) and HIV-infected primary T cells
synergize to cause intestinal pathobiology. Specifically, we will determine the HIV-dependent mechanisms that
alter T-cell function and disrupt the intestinal barrier. In addition, we will identify the pathways altered in IECs
exposed to HIV infected T-cells that lead to barrier dysfunction. Findings generated from these studies will
allow a better understanding of the mechanisms underlying HIV related enteropathy that is known to be a
major source of morbidity and mortality in HIV-infected individuals and will lead to development of new
strategies to improve the health of HIV infected people.
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## Key facts

- **NIH application ID:** 10454418
- **Project number:** 5R01DK129058-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kathleen L. Collins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $748,281
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454418

## Citation

> US National Institutes of Health, RePORTER application 10454418, Molecular mechanisms underlying HIV related intestinal epithelial barrier dysfunction (5R01DK129058-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10454418. Licensed CC0.

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