Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.
Biochem Pharmacol
; 194: 114816, 2021 12.
Article
in En
| MEDLINE
| ID: mdl-34715067
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).
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HIV-1
/
Drug Delivery Systems
/
Protein Kinase Inhibitors
/
Cell Proliferation
/
Homeostasis
/
Antigens, Viral
Type of study:
Clinical_trials
Limits:
Humans
Language:
En
Journal:
Biochem Pharmacol
Year:
2021
Document type:
Article
Affiliation country:
United States