Background
Despite suppressive ART, residual inflammation persists in people with HIV (PWH), thus driving higher risk of SNAEs and mortality. Circulating HIV proteins have been detected in some suppressed PWH, as an expression of the persistence of translation-competent proviruses. We therefore seek to investigate whether peripheral inflammation and mortality risk are associated with production of p24 in PWH on suppressive ART.
Methods
PWH on suppressive ART (HIV-RNA <20 cp/mL) and age/sex-matched healthy controls without HIV were enrolled. We cross-sectionally measured ultra-low level serum p24 (Simoa), 12 plasma markers of inflammaging (IP-10/TNF-α/IL-2/IL-4/IL-17A/IL-6/IL-8/sCD14/sCD163/TIMP-1/GDF-15/ROMO-1) [Luminex], and activated (CD38+) CD8+ T-cells (flow cytometry). Mortality risk was estimated by VACS Index 2.0. Mann-Whitney test and linear regression were used for analysis.
Results
120 PWH and 20 controls were recruited. PWH (83.3% males) had a median age of 54 (IQR 47–59) years. They were on ART for 10 (6–19) years, with a current CD4 T-cell count of 725 (504–908) cells/μL.
Compared to controls, PWH showed higher IP-10/TNF-α/IL-17A/IL-8/sCD14/sCD163/TIMP-1/GDF-15. VACS Index 2.0 was positively associated with IP-10/TNF-α/sCD14/sCD163/TIMP-1/GDF-15/CD8+CD38+. Yet, by fitting a multivariable regression model including all these seven markers, only IP-10, GDF-15 and CD8+CD38+ confirmed independently associated with VACS Index 2.0.
By setting the p24 positivity cut-off at 0.025 pg/mL based on the mean+3SD of controls, 25 (20.8%) PWH had detectable p24 (median 0.0516 pg/mL; range 0.0264–0.8280 pg/mL) (Fig.1A).
When assessing inflammaging markers in PWH according to p24 detectability, p24+ PWH showed significantly higher IP-10 levels. Accordingly, soluble p24 was positively associated with IP-10 at both univariable and multivariable (adjusted for sex, age, CD4 T-cell count, ART duration) regression analysis (Fig.1B). Conversely, no association was found between soluble p24 and CD38+CD8+ T-cells.
Conclusions
Despite long-term suppressive ART, ultra-low level soluble p24 is detectable in ~20% PWH and associated with higher circulating IP-10, a pro-inflammatory chemokine involved in the recruitment of innate and adaptive immune cells into sites of 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.