Inhibition of Stemness Pathways during Acute SIV Limits Infection of Central Memory CD4+ T Cells and Alters Viral Reservoir Activity in Macaques

Authors

Hamid, R., Ruiz-Salinas, I., Schoof, N., Colvin, A., Tao, S., Hurwitz, S. J., Lin, A., Goldy, J., Tharp, G. K., Bosinger, S. E., Schinazi, R. F., Silvestri, G., Chahroudi, A., Mavigner, M.

Abstract

The establishment of a reservoir of latently infected CD4+ T cells that persist on antiretroviral therapy (ART) through proliferation represents the main barrier to HIV cure. Here, we evaluated in macaques a therapeutic approach targeting Wnt and Notch pathways that regulate T cell proliferation and differentiation during acute SIV infection, when the viral reservoir is seeded. The combination of PRI-724 and LY3039478 led to reprogramming of central memory CD4+ T cells away from quiescence and stemness toward a metabolically active effector profile resulting in reduced infection of central memory CD4+ T cells. Following sustained ART, levels of SIV RNA in CD4+ T cells were higher in the PRI-724 + LY3039478-treated group compared to controls, although SIV DNA was similar. These findings suggest that stemness pathway inhibition promotes memory T cell differentiation leading to a more transcriptionally active reservoir and has potential to synergize with "shock-and-kill" approaches to reduce HIV persistence.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Jul 2026.

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