Associations Between Immune Senescence and Immune Reconstitution Among People Living With HIV Undergoing Antiretroviral Therapy

BACKGROUND: Failure of immune reconstitution (IR), characterized by suboptimal CD4⁺ T-cell recovery despite virologic suppression on antiretroviral therapy (ART), remains a critical challenge for people living with human immunodeficiency virus (PLWHIV). The contribution of immune senescence to this failure is incompletely understood. OBJECTIVE: This study aimed to determine the role of pre-ART immune senescence characterized by lymphocyte profile and lymphocyte cellular senescence markers in nonimmune reconstitution (NIR) after 48 weeks of ART initiation. METHODS: We first performed a SenMayo gene set score from publicly available CD4⁺ T-cell scRNA-seq data. Subsequently, a prospective cohort of 510 ART-initiating PLWHIV was assessed at baseline and week 48. IR was strictly defined as a CD4⁺ T-cell count increase over 350 cells/uL. Logistic regression; immunophenotyping; cytokine profiling, including TNF-α, IFN-γ and CD-107a; and cellular senescence marker, including p16, p21, p53, and senescence-associated β-galactosidase assessments identified NIR factors. RESULTS: Bioinformatics analysis revealed multiple ART-naïve CD4⁺ T-cell subtypes exhibited elevated cellular senescence scores. Patients with IR were significantly younger than those with NIR (both in AIDS and non-AIDS subcohorts, p < 0.05). Multivariable analysis indicated age was an independent risk factor for NIR. Before ART initiation, the NIR group exhibited a distinctly senescent immune profile characterized by reduced naïve T cells, increased terminally differentiated T cells, and heightened chronic inflammation with elevated cytokine secretion. ART failed to fully reverse these immune abnormalities, and cellular senescence was most pronounced in CD4⁺ T cells within the NIR group prior to treatment. CONCLUSION: Pre-ART immune senescence is strongly associated with NIR in PLWHIV receiving ART. These findings necessitate considering immunological age and immune senescent status for personalized therapeutic strategies.