Expression characteristics of the cGAS–STING pathway in individuals coinfected with HIV and Mycobacterium tuberculosis

Coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (MTB) is characterized by severe immune dysfunction and poor clinical outcomes, but its underlying mechanisms are not fully defined. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway is a key innate immune pathway involved in cytosolic DNA sensing and induction of type I interferon responses. Although this pathway has been studied separately in HIV and tuberculosis, its expression profile and immunological significance in HIV/MTB coinfection remain unclear. We therefore investigated its expression characteristics and association with T-cell immune dysfunction in individuals with HIV/MTB coinfection. This cross-sectional study included 69 participants. Peripheral blood mononuclear cells were collected for transcriptomic sequencing and flow cytometric analysis. Differential gene expression was analyzed using edgeR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, gene set enrichment analysis, and protein-protein interaction network analysis were performed to identify core pathways and key regulatory genes associated with HIV/MTB coinfection. Flow cytometry was used to assess T-cell activation, exhaustion, apoptosis, and expression of cGAS-STING pathway components in T lymphocytes. Transcriptomic analysis revealed that HIV/MTB coinfection was associated with pronounced enrichment in cytosolic DNA-sensing (hsa04623) and interferon-related pathways. PPI network analysis identified multiple hub genes related to cell cycle regulation, apoptosis, and immune dysregulation. Flow cytometric analysis further demonstrated that T-cell activation, exhaustion, and apoptosis markers were significantly increased in the coinfection group, and activation markers were positively correlated with exhaustion and apoptosis. Within activated CD38⁺ T-cell subsets, coinfected individuals showed increased STING and IRF3 expression in CD4⁺ T cells and increased STING expression in CD8⁺ T cells. whereas no significant increases were observed in PD-1⁺ or TIGIT⁺ T cells. In addition, Caspase-3 levels were positively correlated with TBK1 and IRF3 in CD4⁺ T cells and with STING and IRF3 in CD8⁺ T cells. HIV/MTB coinfection is characterized by pronounced T-cell immune dysregulation and distinct transcriptional alterations. Activation of the cGAS-STING signalling pathway was associated with T-cell activation and apoptosis in coinfected individuals, suggesting that cGAS-STING-mediated immune responses may contribute to the immunopathogenesis of HIV/MTB coinfection and could serve as a potential target for immunotherapeutic intervention.