Antiretroviral therapy (ART) has significantly extended the life expectancy of people with HIV (PWH), rendering population ageing and immunosenescence prominent clinical priorities. T-cell senescence is linked to mitochondrial dysfunction and drives age-related immune remodelling, yet how HIV infection and ageing jointly shape CD4 + and CD8 + T-cell immunophenotypes and mitochondrial remodelling remains unclear. This cross-sectional study included 61 PWH on suppressive ART for ≥12 months and 61 age- and sex-matched HIV-negative men who have sex with men, stratified into younger (≤ 35 years) and older (≥ 50 years) groups. Multiparameter flow cytometry was used to profile CD4 + and CD8 + T-cell differentiation, stemness, activation/exhaustion, and metabolic phenotypes, together with mitochondrial mass and membrane potential. We found that ageing and HIV infection were associated with T-cell remodelling, characterized by expanded late-differentiated phenotypes and reduced stem-like, homeostatic and costimulatory CD4 + and CD8 + T-cell subsets, as indicated by upregulated CD57 and CX3CR1 and downregulated CD45RA + CD31 + , FOXO1, and CD28. Notably, younger PWH had an ageing-like CD4 + T-cell profile, with higher CD57, CX3CR1 and TIGIT expression than younger HIV-negative individuals. In contrast, HIV-related CD8 + T-cell perturbations (KLRG1, NKG2C and CD95) were more pronounced in older PWH. PWH exhibited increased mitochondrial mass and membrane potential in both total and senescent-like CD4 + and CD8 + T cells, particularly in CD8 + T cells from older PWH. In CD4 + T cells, KLRG1 and CX3CR1 expression correlated positively with age, and inversely with CD4 + T-cell counts and CD4/CD8 ratio. By contrast, FOXO1 expression in CD8 + T cells was inversely associated with age, late-differentiation markers, and ART duration in PWH. Overall, age is a major driver of T-cell immunosenescence, and HIV infection modulates and exacerbates these alterations. Mitochondrial stress, FOXO1 downregulation and immune network remodelling support a multifaceted model of HIV-associated immune ageing that may contribute to heterogeneous immune reconstitution in PWH, highlighting potential targets to mitigate immune ageing. T-cell remodelling associated with ageing and HIV infection. Ageing and HIV infection are associated with remodelling of CD4 + and CD8 + T cell-phenotypes, characterized by enhanced late-differentiation markers, reduced stem-like and costimulatory features, and dysregulated mitochondrial profiles. • Age and HIV jointly induce multidimensional remodelling of CD4 + and CD8 + T cells to senescent phenotypes. • Dual exposure drives depletion of stem-like and costimulatory T-cell subsets. • PWH on suppressive ART show elevated mitochondrial mass and membrane hyperpolarization, especially in CD27 - CD57 + T cells. • FOXO1 + T-cell frequencies in PWH inversely correlate with age, late differentiation, and ART duration. • Higher frequencies of KLRG1 + /CX3CR1 + CD4 + T cells are associated with lower CD4 T-cell counts.
Jin et al. (Fri,) studied this question.