# Impact of HIV/SIV Infection on Paneth and Intestinal Stem Cell Interaction

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $776,916

## Abstract

PROJECT SUMMARY
Worldwide more than 90% of all HIV infections occur via mucosal route. The gastrointestinal tract is a site of
massive CD4 T-cell depletion, viral infection, enterocyte apoptosis, disruption of epithelial tight junctions
leading to microbial translocation, and lymphoid tissue fibrosis. The SIV infected rhesus macaque (RM) model
is considered a well-accepted model to study of HIV-associated enteropathy and we have recently discovered
that intestinal epithelial cell (iEC) apoptosis and diminished iEC regeneration occur soon after SIV-infection.
Internalization of IL-10R with the resultant impact on IL-10 signaling and dysregulation of the IL-10-mediated
anti-inflammatory responses also play a crucial role in iEC damage and subsequent SIV pathogenesis.
Understanding the aberrant iEC regeneration in HIV/SIV might lead to an alternative approach for the
treatment of HIV-mediated enteropathy based on enhancing iEC repair mechanisms. In the small intestine,
each intestinal villus is encircled by at least six crypts of Lieberkühn, which house dedicated populations of
stem and progenitor cells that self-renew, as well as give rise to the various differentiated iECs. LGR5+ (Leu-
rich repeat containing G protein-coupled receptor 5) was identified as the marker for crypt base columnar
(CBC) stem cells that was selectively expressed at the base of adult intestinal crypts. Genetic analysis of
LGR5+ intestinal stem cells (ISCs) revealed that a single stem cell leads to crypt homeostasis in adult
intestines by clonal expansion. Stem cells give rise to the polarized enterocytes, goblet cells, enteroendocrine
cells, and tuft cells that migrate up to the villi after passing through several transiently-amplifying (TA) stages.
TA cells also terminally differentiate into Paneth cells (PCs), a highly specialized secretory cell type which
intersperse with stem cells at the base of the crypts in the small intestine. Recent cell ablation and co-culture
studies showed that PCs provide essential niche signals to support LGR5+ stem cell renewal and survival.
Therefore, we hypothesize that HIV/SIV infection disrupts the communication between LGR5+ ISC and
PCs leading to diminished iECs regeneration. In Aim 1, we will define the correlates of LGR5+ stem cells
and PCs with SIV/HIV infection status. In Aim 2, we will uncover the alterations of ISCs and PCs
communication in SIV infection in two sub aims. In Sub-Aim 2a, we will determine the transcriptional
programming of ISCs and PCs in normal and SIV infected RMs. In Sub-Aim 2b, we will compare the colony
forming efficiency of rhesus intestinal LGR5+ stem cells between SIV infected and normal RMs.

## Key facts

- **NIH application ID:** 9878838
- **Project number:** 5R01DK109883-04
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** PETER J DIDIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $776,916
- **Award type:** 5
- **Project period:** 2017-03-05 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878838

## Citation

> US National Institutes of Health, RePORTER application 9878838, Impact of HIV/SIV Infection on Paneth and Intestinal Stem Cell Interaction (5R01DK109883-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9878838. Licensed CC0.

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