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.