# Exploring the role of the Wnt/B-catenin signaling pathway on HIV reservoir

> **NIH NIH R56** · EMORY UNIVERSITY · 2021 · $871,843

## Abstract

ABSTRACT
The key obstacle to cure HIV infection is a reservoir of latently-infected memory CD4+ T cells that persist despite
long-term ART and is maintained though cellular proliferation. This latent reservoir involves a heterogeneous
population of memory CD4+ T cell subsets at various differentiation stages. Each subset displays a distinct
proliferative capacity, HIV transcriptional activity, and viral inducibility. Cells presenting a differentiated
phenotype account for the majority of clonal expansions in the reservoir. However, such expended clones often
wax and wane and the core of HIV reservoir likely lies in multipotent memory CD4+ T cells with high survival and
self-renewal abilities such as central (CM) and stem cell memory (SCM) CD4+ T cells.
The Wnt/β-catenin signaling pathway regulates the balance between self-renewal and differentiation of these
long-lived memory CD4+ T cells. We recently showed that inhibition of the interaction of β-catenin with the
transcriptional coactivator CPB decreased the proliferation of SCM and CM CD4+ T cells and modified their
transcriptome towards a more differentiated phenotype in ART-suppressed SIV-infected rhesus macaques
(RMs). The Wnt/β-catenin signaling pathway has also been implicated in HIV replication suppression with a
potential role of CD8+ T cell secretion of Wnt ligands. The objective of this application is to investigate this dual
role of the Wnt/β-catenin signaling pathway on HIV persistence with the central hypothesis that pharmacological
targeting of two critical steps of the Wnt/β-catenin pathway can alter HIV reservoir maintenance by (i) interfering
with the self-renewal ability of SCM and CM CD4+ T cells, and (ii) alleviating HIV transcriptional repression. Using
the highly relevant model of SIV-infected ART-treated RMs, we will address this hypothesis in three Specific
Aims. In Aim 1, we will characterize the impact of the pharmacological modulation of β-catenin-mediated
transcription on memory CD4+ T cell dynamics and SIV reservoir composition. In Aim 2, we will assess if the
transient induction of long-lived memory CD4+ T cell differentiation potentiate the activity of a latency reversing
agent. In Aim 3, we will explore the effect of Wnt ligand secretion blockade on long-lived memory CD4+ T cell
self-renewal and SIV latency.
The proposed experiments build upon an appreciation of the immunologic complexity of CD4+ T cell reservoir
dynamics. This conceptually innovative work will provide critical new information on the biology of HIV
persistence in memory CD4+ T cells.

## Key facts

- **NIH application ID:** 10436397
- **Project number:** 1R56AI165149-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Maud Mavigner
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $871,843
- **Award type:** 1
- **Project period:** 2021-08-09 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436397

## Citation

> US National Institutes of Health, RePORTER application 10436397, Exploring the role of the Wnt/B-catenin signaling pathway on HIV reservoir (1R56AI165149-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436397. Licensed CC0.

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