Pharmacological Modulation of the Wnt/β-Catenin Pathway Inhibits Proliferation and Promotes Differentiation of Long-Lived Memory CD4+ T Cells in Antiretroviral Therapy-Suppressed Simian Immunodeficiency Virus-Infected Macaques

Abstract

The major obstacle to human immunodeficiency type 1 virus (HIV-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and is maintained through cellular proliferation. Long-lived memory CD4⁺ T cells with high self-renewal capacity, such as central memory (CM) T cells and stem cell memory (SCM) T cells, are major contributors to the viral reservoir in HIV-infected individuals on ART. The Wnt/β-catenin signaling pathway regulates the balance between self-renewal and differentiation of SCM and CM T cells, and pharmacological manipulation of this pathway offers an opportunity to interfere with the proliferation of latently infected cells. Here, we evaluated in vivo a novel approach to inhibit self-renewal of SCM and CM CD4⁺ T cells in the rhesus macaque (RM) model of simian immunodeficiency (SIV) infection. We used an inhibitor of the Wnt/β-catenin pathway, PRI-724, that blocks the interaction between the coactivator CREB-binding protein (CBP) and β-catenin, resulting in the cell fate decision to differentiate rather than proliferate. Our study shows that PRI-724 treatment of ART-suppressed SIV_mac251-infected RMs resulted in decreased proliferation of SCM and CM T cells and modified the SCM and CM CD4⁺ T cell transcriptome toward a profile of more differentiated memory T cells. However, short-term treatment with PRI-724 alone did not significantly reduce the size of the viral reservoir. This work demonstrates for the first time that stemness pathways of long-lived memory CD4⁺ T cells can be pharmacologically modulated in vivo, thus establishing a novel strategy to target HIV persistence.IMPORTANCE Long-lasting CD4⁺ T cell subsets, such as central memory and stem cell memory CD4⁺ T cells, represent critical reservoirs for human immunodeficiency virus (HIV) persistence despite suppressive antiretroviral therapy. These cells possess stem cell-like properties of enhanced self-renewal/proliferation, and proliferation of latently infected memory CD4⁺ T cells plays a key role in maintaining the reservoir over time. Here, we evaluated an innovative strategy targeting the proliferation of long-lived memory CD4⁺ T cells to reduce viral reservoir stability. Using the rhesus macaque model, we tested a pharmacological inhibitor of the Wnt/β-catenin signaling pathway that regulates T cell proliferation. Our study shows that administration of the inhibitor PRI-724 decreased the proliferation of SCM and CM CD4⁺ T cells and promoted a transcriptome enriched in differentiation genes. Although the viral reservoir size was not significantly reduced by PRI-724 treatment alone, we demonstrate the potential to pharmacologically modulate the proliferation of memory CD4⁺ T cells as a strategy to limit HIV persistence.

Keywords: PRI-724; SIV; Wnt/β-catenin pathway; memory CD4+ T cells; proliferation; stemness.