Background
Dasatinib (DASA), a tyrosine kinase inhibitor (TKI) used to treat chronic myeloid leukemia, may help promote HIV-1 latency and reduce immune activation and senescence. However, DASA could impact T-cell effector functions by inhibition of TCR proximal kinases. Its impact on antigen-specific responses in people with HIV (PWH) is unclear. We evaluated the impact of low-dose DASA (70 mg QD for 24 weeks) on HIV- and CMV-specific T cells in a randomised, double-blind, placebo-controlled clinical trial in 60 ART-suppressed PWH (BCN04-DASA; NCT05780073).
Methods
Data from 28 participants receiving DASA and 20 receiving placebo were analysed at baseline and week 24 (end of treatment). Multiparametric flow cytometry was performed following in vitro stimulation with HIV Gag and CMV pp65 peptide pools to assess the frequencies of antigen-specific T cells (CD69, CD154), cytotoxic capacity (CD107, Perforin, and Granzyme B), and cytokine production (TNFα, MIP1β, IFNγ, and IL-2). Data were integrated with results on primary/secondary endpoints of the study (pSAMHD1 and reservoir).
Results
There was a significant reduction from baseline to week 24 in the frequencies of IFNγ–producing CD8 T cells and TNFα–producing CD4 T cells upon Gag stimulation in the DASA (p<0.05) but not in the Control group. Similarly, polyfunctionality analyses revealed that the proportions of Gag-specific CD8 T cells exerting ≥3 functions also declined after DASA (p=0.01). At week 24, Gag-specific CD8 T cells expressed significantly lower levels of IL-2 in the DASA vs Control Group (p=0.02). In contrast, there were no significant changes in the frequencies of cytokine-producing CMV-specific T cells in either study group. As also reported, there was no reduction in intact/total proviral DNA or CA-RNA levels during DASA treatment.
Conclusions
Low-dose DASA reduced the frequencies of cytokine-expressing HIV-specific CD4/CD8 T cells in ART-suppressed PWH while preserving CMV-specific immunity. This differential effect on Gag- and CMV pp65-specific T cells likely reflects distinct susceptibilities of different antigen-specific T-cell subsets to DASA, suggesting that its activity might not be broadly immunosuppressive. The reduced CD8 polyfunctionality is consistent with the limited reservoir clearance observed in the study. Overall, these results point at a selective immunomodulatory effect of DASA that warrants further consideration to understand the potential effect of TKIs in containing rebound viremia in cure trials.