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• W3208366838 endingPage "114816" @default.
• W3208366838 startingPage "114816" @default.
• W3208366838 abstract "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 γc-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 γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >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 iswell tolerated in patients with chronic myeloid leukemia (CML)." @default.
• W3208366838 created "2021-11-08" @default.
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• W3208366838 date "2021-12-01" @default.
• W3208366838 modified "2023-10-17" @default.
• W3208366838 title "Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence" @default.
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• W3208366838 doi "https://doi.org/10.1016/j.bcp.2021.114816" @default.
• W3208366838 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8629953" @default.
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• W3208366838 hasPublicationYear "2021" @default.
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