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

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.

Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo

“…We next evaluated the latency reversal activity of AZD5582 in twenty-one Mamu-B*08 and –B*17 negative rhesus macaques (RMs) infected with SIV mac239 and treated with a potent ART regimen containing tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and dolutegravir (DTG) initiated eight weeks post infection ( Fig. 3a and Supplementary Table 7 ) 49 and 50 . Suppression of SIV viremia below 60 copies/mL (standard assay limit of detection) was achieved in all animals in two to 20 weeks and ART was continued for 55 to 67 weeks prior to further treatment ( Fig.…”

Pharmacological suppression of glycogen synthase kinase-3 reactivates HIV-1 from latency via activating Wnt/β-catenin/TCF1 axis in CD4 + T cells

“…Of note, Wnt/β-catenin signalling modulates the proliferation of CD4 + T cells that form long-lived HIV-1 reservoir. Blockade of the interaction between β-catenin and co-activator CREB-binding protein, by a Wnt/β-catenin pathway small molecule inhibitor PRI-724, decreases the proliferation of stem cell memory- and central memory-CD4 + T in ART-suppressed SIV mac251 -infected rhesus macaques, but unable to not significantly reduce the viral reservoir size [ 45 ].…”

Stem cell-like memory T cells: The generation and application

“…In the rhesus macaque model of SIV infection, antiretroviral therapy induced substantial decline of SIV DNA level in CD4 Tem in both blood and lymph nodes by approximately 100‐fold, but SIV DNA levels remained unchanged in CD4 Tcm and Tscm 93 . Using Wnt/β‐catenin pathway inhibitor PRI‐724, the proliferation of SIV‐infected CD4 Tscm and Tcm were significantly restricted, although the size of HIV reservoir did not shrink significantly by PRI‐724 alone 93 . The proliferation of HIV‐infected CD4 Tscm can also be inhibited by blocking IL‐15 receptor signaling with JAK inhibitor.…”

“…CD4 Tscm are suggested to be a latent reservoir of HIV and become a disadvantageous factor for eliminating HIV in patients 92 . In the rhesus macaque model of SIV infection, antiretroviral therapy induced substantial decline of SIV DNA level in CD4 Tem in both blood and lymph nodes by approximately 100‐fold, but SIV DNA levels remained unchanged in CD4 Tcm and Tscm 93 . Using Wnt/β‐catenin pathway inhibitor PRI‐724, the proliferation of SIV‐infected CD4 Tscm and Tcm were significantly restricted, although the size of HIV reservoir did not shrink significantly by PRI‐724 alone 93 .…”