STING-mediated JAK-STAT suppression drives CD4⁺ T cell dysfunction in aging people living with HIV-1

Abstract Background The rapidly growing population of older people living with HIV-1 (PLWH) continues to experience persistent immune dysfunction despite viral suppression, yet the underlying mechanisms remain unclear. Methods To investigate the molecular basis of the unique immunological defects in these elderly PLWH, we performed time-course transcriptomic analysis of CD3/CD28-stimulated CD4⁺ T cells from 58 participants (stratified by age and HIV status), validated through flow cytometry, qPCR, and cytokine profiling in 120 subjects. Gene modulated Jurkat cell models and pharmacological inhibition experiments were employed to dissect mechanistic pathways. Results Our results demonstrate that activated CD4⁺ T cells from older PLWH exhibited broad suppression of TNF, NF-κB and IL-17 signaling pathways, with 40 critical genes showing co-regulation by aging and HIV-1. Among them, the expression of stimulator of interferon genes (STING) was significantly elevated in older PLWH, correlating with CD4⁺ T cell depletion. Mechanistically, STING hyperactivation induced src homology 2 containing protein tyrosine phosphatase 1/2 (SHP-1/2) phosphorylation, which suppressed Janus kinase 1 (JAK1)-mediated phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1), thereby reducing IFN-γ production. STING inhibition with H151 restored IFN-γ secretion (3.1-fold increase) while reducing T cell activation markers (CD25⁺Ki67⁺ cells). Moreover, STING hyperactivation induced classical T cell exhaustion, characterized by TIM-3 upregulation, TOX-centered transcriptional programming, and loss of polyfunctional cytokine output; these changes were reversed by STING inhibition. Conclusion This study identifies STING-mediated JAK-STAT suppression as a novel mechanism of immune dysfunction in aging PLWH, proposing targeted STING inhibition as a potential therapeutic strategy to improve immune recovery in this vulnerable population (Graphical abstract).