Accelerated immune senescence in people living with HIV: a systematic review of mechanisms, biomarkers and implications for healthy aging

Background Despite effective antiretroviral therapy (ART), many people living with HIV (PLWH) exhibit persistent immune dysfunction associated with premature biological aging. This review synthesized evidence on the mechanisms, biomarkers and clinical implications of HIV-associated immunosenescence. Methods PubMed, Scopus, Web of Science and Embase were searched from inception to 11 July 2026. Original human studies examining biological mechanisms, biomarkers or clinical manifestations of immunosenescence among adults living with HIV were eligible. Study selection, data extraction and methodological appraisal followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and design-specific Joanna Briggs Institute (JBI) criteria. Findings were synthesized narratively because of substantial clinical and methodological heterogeneity. Results Thirty-seven studies were included. Persistent T-cell activation and altered differentiation were the most consistently reported immune-aging features. Frequently evaluated parameters included the CD4/CD8 ratio; loss of CD28; expression of CD57, programmed cell death protein 1 (PD-1) and killer cell lectin-like receptor G1 (KLRG1); co-expression of CD38 and human leukocyte antigen-DR (HLA-DR); interleukin-6 (IL-6), C-reactive protein (CRP), soluble CD14 (sCD14) and soluble CD163 (sCD163); microbial-translocation markers; telomere length; and emerging epigenetic, mitochondrial and senescence-associated secretory phenotype measures. Cytomegalovirus (CMV)-related immune responses were associated with highly differentiated T-cell populations in several studies, although generalized T-cell activation remained the stronger independent correlate in some adjusted analyses. Immune-aging biomarkers were associated with incomplete immune recovery, frailty and non-AIDS morbidity, but heterogeneous definitions and predominantly cross-sectional designs limited causal inference and direct comparison. Certainty was moderate for persistent T-cell activation and differentiated T-cell phenotypes, low for most inflammatory, microbial-translocation, CMV and clinical associations, and very low for emerging molecular biomarkers. Conclusion HIV-associated immunosenescence comprises overlapping cellular, inflammatory and molecular abnormalities that may persist during suppressive ART. Longitudinal studies using standardized definitions are required to validate parsimonious biomarker panels, establish temporality and determine whether biomarker-guided interventions improve healthy-aging outcomes among PLWH.