DDIT4 upregulation associates with gammadelta T Cells dysfunction in ART-suppressed people living with HIV-1

BACKGROUND: Antiretroviral therapy (ART) effectively suppresses HIV-1 replication, yet T cell dysfunction persists in ART-suppressed people living with HIV-1 (PLWH). While mammalian target of rapamycin (mTOR) signaling drives T cell dysregulation, the role of DNA damage-inducible transcript 4 (DDIT4), a stress-induced mTOR inhibitor, in HIV-1 infection remains undefined. In this study, we aimed to investigate the expression of DDIT4 in immune cells, and clarify its associations with T cell dysfunction in ART-suppressed PLWH. METHODS: We enrolled 24 ART-suppressed PLWH and 16 people living without HIV (PWoH). DDIT4 mRNA expression in peripheral blood mononuclear cells (PBMCs) was quantified by RT-qPCR. Flow cytometry was employed to assess DDIT4 protein expression together with T cell activation, exhaustion, and senescence markers. RESULTS: DDIT4 transcriptional expression was significantly elevated in ART-suppressed PLWH and positively correlated with hemoglobin levels (r = 0.524, P = 0.010). Notably, DDIT4 was markedly upregulated in gammadelta T cells which displayed memory phenotypes with increased CD38, HLA-DR, TIGIT, and CD57 expression, but diminished CD28 expression. Furthermore, the frequency of DDIT4⁺gammadelta T cells was correlated positively with the frequencies of CD28⁻CD57⁺gammadelta T cells, but inversely with CD4⁺ T cell counts, total lymphocytes, and monocytes. CONCLUSIONS: During HIV-1 infection, DDIT4 may act as a stress-responsive checkpoint, inducing gammadelta T cell exhaustion and senescence in ART-suppressed PLWH. These findings highlight the potential of DDIT4 as a therapeutic target to restore gammadelta T cells competence and offer novel insights into ART-refractory immune dysfunction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1186/s12879-026-13258-x.