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

• Type of Material: Article
• Authors: Maud Mavigner, Emory University; M. Zanoni, Emory University; G.K. Tharp, Emory University; J. Habib, Emory University; C.R. Mattingly, Emory University; M. Lichterfeld, Massachusetts Institute of Technology; M.T. Nega, Emory University; Thomas Vanderford, Emory University; Steven Bosinger, Emory University; Ann Chahroudi, Emory University
• Language: English
• Date: 2020-01-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Mavigner et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01094-19
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 94
• Issue: 1
• Grant/Funding Information: This work was supported by amfAR ARCHE Award 108905-56-RGRL (to A. Chahroudi), amfAR Innovation Grant 109353-59-RGRL (to M. Mavigner), NIH grant R56 AI117851 (to A. Chahroudi), the Yerkes Pilot Program (to A. Chahroudi), grant P30 AI050409 (Emory CFAR), and grant RR000165/OD011132 (Yerkes National Primate Research Center).
• Keywords: SIV; STABILITY; REPLICATION; SHOCK; Life Sciences & Biomedicine; HIV RESERVOIR; SURVIVAL; Science & Technology; stemness; Virology; PRI-724; LATENT RESERVOIR; memory CD4(+) T cells; PERSISTENCE; proliferation; Wnt/beta-catenin pathway; DRIVEN
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

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 ARTsuppressed SIVmac251-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 reser- voir 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.