# Mechanisms of HIV-associated epithelial  intestinal stem cell (ISC) dysfunction

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $711,945

## Abstract

SUMMARY
The gastrointestinal (GI) tract is a major site of Human Immunodeficiency Virus (HIV) replication, which leads to
intestinal inflammation, CD4+ T cell depletion and gut epithelial barrier dysfunction. These defects are thought
to drive HIV disease progression by allowing translocation of luminal microbial products into the circulation, which
triggers chronic systemic immune activation and disease progression. Although antiretroviral therapy (ART)
effectively suppress viral replication in the blood, it does not restore CD4+ T cell levels in the gut; even individuals
with suppressed viral loads for decades have persistent gut barrier impairment and continued microbial
translocation. Epithelial intestinal stem cells (ISCs) are responsible for replenishing the intestinal epithelium
during normal homeostatic turnover and orchestrating epithelial repair following injury. Current studies of
intestinal epithelial dysfunction in HIV are limited and have relied primarily on correlative observations based on
histology or peripheral biomarkers. Our proposal addresses critical gaps in knowledge by 1) performing in-depth
characterization of ISC proliferation, self-renewal and differentiation ex vivo and in vivo in HIV-infected and
uninfected individuals; 2) utilizing tissue samples from a unique cohort of individuals in sub-Saharan Africa,
where HIV burden is highest and most devastating; 3) applying cutting-edge techniques to uncover molecular
signalling pathways involved in HIV-induced epithelial dysfunction; and 4) thoroughly testing mechanistic
hypotheses using relevant mouse models and ex vivo organoid culture systems. With our combined expertise in
HIV disease, mucosal immunology and GI pathology, we are well positioned to uncover specific mechanisms
that underlie intestinal epithelial dysfunction in HIV infection. An understanding of these mechanisms is critical
to facilitate development of novel therapeutic approaches to improve health outcomes of people living with HIV.
In this proposal, we hypothesize that HIV infection results in hyperproliferation of ISCs, aberrant ISC
differentiation, increase epithelial death, and dysfunction of epithelial cellular junction integrity. Additionally,
based upon our data, we hypothesize that this HIV-associated ISC dysfunction can occur via two mechanisms:
1) depletion of intestinal CD4+ T cells and loss of specific T helper cytokines that promote intestinal epithelial
homeostasis and 2) type I and II interferon signalling within ISCs in HIV-infected individuals. To address these
hypotheses we are proposing two complementary aims. Aim 1 will use state-of-the-art technologies to
characterise ISC function directly ex vivo in gut pinch biopsies sampled throughout the intestinal mucosa from
our established cohort at Albert Luthuli Central Hospital in Durban, South Africa. In Aim 2 will use in vivo mouse
models of CD4+ T cell depletion and examine the impact on ISC proliferation, self-renewal and differentiation,...

## Key facts

- **NIH application ID:** 10201595
- **Project number:** 5R01DK126545-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Henrik Kloverpris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $711,945
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201595

## Citation

> US National Institutes of Health, RePORTER application 10201595, Mechanisms of HIV-associated epithelial  intestinal stem cell (ISC) dysfunction (5R01DK126545-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201595. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*