ULTRA-LOW LEVEL SOLUBLE P24 IS ASSOCIATED WITH INFLAMMATION IN PEOPLE WITH HIV ON LONG-TERM VIROLOGICALLY SUPPRESSIVE ANTIRETROVIRAL THERAPY

Introduction: Despite virologically suppressive antiretroviral therapy (ART), residual inflammation persists in people with HIV (PWH), thus driving higher risk of serious non-AIDS events (SNAEs) and mortality. Circulating HIV proteins have been detected in some suppressed PWH, as an expression of the persistence of the translation-competent reservoir. We therefore seek to investigate whether peripheral inflammation and mortality risk are associated with p24 production in this population. Methods: PWH on suppressive ART and age/sex-matched healthy controls without HIV were enrolled. Ultra-low level serum p24 was cross-sectionally (baseline) and longitudinally (6 and 12 months) quantified by Simoa following immune complexes dissociation. In addition, the following were cross-sectionally measured at baseline: plasma biomarkers of inflammaging (Luminex/ELISA), CD38+CD8+ T-cells (flow cytometry), cell-associated total/unintegrated/integrated HIV DNA (qPCR). Mortality risk was estimated by VACS Index 2.0. In vitro experiments tested whether p24 modulates IP-10 secretion by PBMCs. Results: 120 PWH and 20 controls were recruited. PWH exhibited a distinct inflammaging profile characterised by elevated IP-10, TNF-α, IL-17A, IL-8, sCD14, sCD163, TIMP-1, and GDF-15 compared to controls. Several biomarkers were associated with the VACS Index 2.0 in univariable analyses, but only IP-10 and GDF-15 remained independently associated in multivariable modelling. Soluble p24 was detectable in 25/120 (20.8%) PWH at baseline (median: 0.0516 pg/mL; range: 0.0264–0.8280 pg/mL), and its detectability was associated with male sex yet not with immunological parameters or HIV DNA. Among inflammaging biomarkers, p24 was associated exclusively with higher plasma IP-10, both as categorical and continuous variable, even after adjustment for sex, age, CD4 T-cell count, and ART duration. Longitudinal analyses in a subset of 30 PWH revealed dynamic p24 patterns, with persistently p24-positive PWH exhibiting the highest baseline IP-10 levels. In vitro, p24 alone did not induce IP-10 secretion, but in the presence of IFN-γ and TNF-α, it produced a modest yet significant increase, supporting a context-dependent proinflammatory effect. Conclusions: These findings demonstrate that a subset (~21%) of virologically suppressed PWH produce detectable levels of soluble p24, and that this residual HIV protein expression is selectively associated with heightened IP-10–mediated inflammation. Given the positive association between IP-10 and VACS Index 2.0, a measure of physiologic frailty and risk of death, these data suggest that p24-driven inflammation may contribute to SNAEs and mortality in virologically suppressed PWH.