Background
Dasatinib, a proposed senolitic drug and HIV-1 latency promoter, may affect long-lived macrophage reservoirs that maintain viral persistence in tissues despite suppressive ART. We evaluated if low-dose dasatinib alters the functionality and susceptibility to HIV-1 infection of monocyte-derived macrophages (MDMs) in ART-suppressed PWH.
Methods
A subgroup of 12 participants were randomly selected from trial BCN04-DASA (NCT05780073). CD14+ cells were isolated from PBMCs of participants (n=6 dasatinib 70mg QD, n=6 placebo), differentiated ex vivo into MDMs, and infected in vitro with DHIV-GFP to monitor real-time infection by high-content time-lapse confocal microscopy. JR-FL_renilla infection tracked proviral integration and transcription. Co-culture with Candida albicans estimated lipid oxidation with BODIPY. Flow cytometry assessed markers of innate immune sensing, T-cell activation, HIV transcription (p24-gag via KC57), and SAMHD1 phosphorylation status. Oxidative burst (NADPH and ROS) was measured by chemiluminescence. Cytokines for M1/M2 polarization were measured by Luminex.
Results
Dasatinib-treated MDMs showed reduced susceptibility to infection with DHIV-GFP and JR-FL_renilla, correlating with reduced pSAMHD1 (2.2-fold; p=0.0242). DC-SIGN expression was also 3.7-fold lower in the dasatinib-treated group (p=0.0220), suggesting that dasatinib may limit HIV-1 entry into macrophages. Functionally, lipid oxidation and yeast phagocytosis were similar between cohorts, and although NADPH levels were also unchanged, ROS levels were reduced in dasatinib-treated MDMs (3.4-fold, p=0.0200), which may indicate that dasatinib may lower oxidative stress and inflammation while preserving essential macrophage functions. No significant changes were observed in levels of IFNγ, TNFα, or M1/M2-related cytokines.
Conclusions
Low-dose dasatinib modulates MDMs in ART-suppressed PWH by reducing HIV-1 susceptibility, associated with decreased pSAMHD1 and DC-SIGN expression, suggesting enhanced intrinsic viral restriction. The concurrent reduction in ROS without changes in lipid oxidation and phagocytic activity indicate a shift toward a more functional, controlled metabolic state, consistent with an anti-inflammatory profile. Together, dasatinib may enhance antiviral defenses of macrophages while limiting inflammation, supporting its potential to constrain long-lived HIV-1 reservoirs.