Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence

The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via yc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/ or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of yc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferation by >65%, with a reduction in viability <45%, ex vivo. In memory CD4 T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and is well tolerated in patients with chronic myeloid leukemia (CML).

Automated summary

This study investigated FDA-approved oncology drugs and found that dasatinib, ponatinib, and trametinib can significantly reduce proliferation of memory CD4 T cells in HIV-infected individuals. Dasatinib, in particular, blocks both homeostatic and antigen-driven proliferation and aids in reducing the reservoir size. By inhibiting STAT5 phosphorylation, dasatinib hinders IL-7 induced proliferation and prevents spontaneous rebound in cells from people living with HIV-1.