Journal
BIOCHEMICAL PHARMACOLOGY
Volume 194, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114816
Keywords
Anticancer agents; gamma c cytokines; Cell proliferation; Homeostatic proliferation; HIV-1 persistence; Tyrosine kinases
Categories
Funding
- NIH [AI143567-02, AG060192-01A1, AI117970]
- Spanish Ministry of Science and Innovation [PID2019-110275RB-I00]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR002538, TL1TR002540]
- NIH: NIAID
- NIH: NCI
- NIH: NICHD
- NIH: NHLBI
- NIH: NIDA
- NIH: NIMH
- NIH: NIA
- NIH: NIDDK
- NIH: NIMHD
- NIH: NIDCR
- NIH: NINR
- NIH: FIC
- NIH: OAR
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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.
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).
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