Plasma biomarkers of immune regulation and senescence are associated with incident skeletal-related events in people with HIV: a case-cohort study.

BACKGROUND

Persistent immune dysregulation in people with HIV (PWH) on antiretroviral therapy (ART) contributes to an increased risk of skeletal-related events (SREs), serving as a critical paradigm for understanding accelerated aging and age-related diseases. We investigated the association between plasma biomarkers of immune regulation and senescence with incident SRE risk and evaluated potential effect modification by sex.

METHODS

In a case-cohort study nested within the Spanish CoRIS cohort (65 incident SRE cases; 252 subcohort, including 5 overlapping cases), we quantified 24 baseline biomarkers of immune checkpoints and senescence-associated secretory phenotype factors. We estimated adjusted hazard ratios (aHR) using Borgan II-weighted cause-specific Cox regression models adjusted for clinical confounders (age, region of origin, prior AIDS diagnosis, CD4 + T-cell count, coinfections, and lifestyle factors). Sex-biomarker interactions were assessed as exploratory endpoints.

RESULTS

Nineteen biomarkers were independently associated with increased SRE risk (p < 0.05 & q < 0.10). Angiogenic factors (VEGF-A; aHR = 1.94; 95% CI, 1.40-2.68), immune checkpoints (PD-L2; aHR = 1.95; 95% CI, 1.09-3.49), and tissue remodeling markers (MMP-1; aHR = 1.91; 95% CI, 1.08-3.39) displayed independent associations, alongside consistent signals for TIM-3, PD-L1, and IL-8. Pairwise correlation analysis demonstrated clustering between checkpoints and inflammatory cytokines. Exploratory interaction analysis indicated that sex modified these associations; signals for seven markers (e.g., IL-1α, VEGF-A) were stronger in females, although the limited number of events warrants caution.

CONCLUSIONS

Circulating biomarkers of immune exhaustion, inflammation, and senescence are independently associated with incident SREs in PWH on long-term ART. Our findings indicate a systemic pro-inflammatory signature and suggest that females exhibit higher sensitivity to inflammatory damage.