Background
Dasatinib, a tyrosine kinase inhibitor approved for chronic myeloid leukemia, has been shown to modulate immune responses and promote NK cell expansion and cytotoxicity. NK cells are critical effectors of innate immunity with the capacity to eliminate HIV-infected CD4⁺ T cells, but their function is often impaired under long-term ART. As viral persistence in latent reservoirs contributes to rebound after ART interruption, strategies that enhance NK cell effector activity are of interest for HIV cure approaches. We aimed to analyze the impact of dasatinib on NK cell function in ART-suppressed people with HIV (PWH).
Methods
PWH on ART and dasatinib 70mg QD or placebo for 24 weeks were randomly selected from participants of NCT05780073 (BCN04-DASA) (Dasatinib n=17; placebo n=16). NK cell-mediated cytotoxicity against GFP HIV-infected TZM target cells was assessed by high-content time-lapse imaging confocal microscopy after 48h co-culture. NK phenotyping and cytokine production upon activation with Hsp70 was measured by flow cytometry. In addition, NK cells from healthy donors (n=3) were treated in vitro with dasatinib for 5 days and relative expression of STAT1 and STAT3 was quantified by qPCR compared to untreated cells.
Results
1) NK cell cytotoxicity, quantified as the percentage reduction in GFP⁺ TZM target cells normalized to NK cell counts after 48h of co-culture, was higher in DASA participants compared to placebo. 2) This enhanced cytotoxicity was accompanied by a significant expansion of CD56⁺CD16⁺GZB⁺ NK cells in DASA participants at week 24, without changes in the Control group. 3) In NK cells from healthy donors, treatment in vitro with dasatinib significantly increased STAT1 expression (2−ΔΔCt >1) and decreased STAT3 expression (2−ΔΔCt <1) relative to untreated cells, suggesting activation of JAK/STAT signaling pathways involved in NK cell effector function.
Conclusions
Low-dose dasatinib treatment in ART-suppressed PWH enhanced NK cell-mediated cytotoxicity against HIV-infected targets, associated with expansion of CD56⁺CD16⁺GZB⁺ NK cells. Mechanistically, dasatinib increases STAT1, promoting NK activation and cytotoxicity, and decreases STAT3, relieving inhibitory signaling and enhancing effector function. These findings support dasatinib as a potential immunomodulatory drug to boost NK cell function in HIV cure approaches.