Background
Chronic inflammation is a critical driver of morbidities and mortality in normal aging. In people with HIV (PWH), inflammation can lead to increased incidence and earlier onset of non-AIDS comorbidities and aging syndromes, such as frailty. Here, we measured plasma markers of inflammation and T cell phenotypes from PWH with and without frailty to investigate immunologic parameters associated with frailty in PWH.
Methods
Inflammatory markers in blood plasma and T cell phenotypes in peripheral blood mononuclear cells (PBMCs) from PWH without frailty (0 Fried score, n=60, 20% female, median age 58 years) and with frailty (≥3 Fried score, n=60, 30% female, median age 59.5 years) were measured by Luminex assay or flow cytometry, respectively. All participants were enrolled in the longitudinal observational HAILO study performed by the ACTG (A5322). Multiple least-squares linear regression analysis was used to determine the association of each marker with frailty when adjusting for age, sex at birth, and race. Spearman correlations were used to determine the association of plasma markers with CD4 T cell phenotypes.
Results
We found that 19 (25.3%) of 75 markers measured in plasma were significantly associated with frailty in adjusted analyses (Figure), most of which are downstream of NF-kB signaling and include IL-6, IL-15, IFNg, and the chemokines IL-8, CCL3, CCL11, and CCL19. In adjusted analyses, the proportion of CD4 T cells with a naïve phenotype was significantly reduced in frail individuals and the proportion of CD4 T cells expressing the activation/exhaustion marker PD-1 was significantly elevated in frail individuals. Of the 19 markers associated with frailty, we found that only osteoprotegerin was significantly correlated with both percent naïve (rho=-0.266, P=0.042) and percent PD-1+ (rho=0.409, P=0.001) CD4 T cells among PWH with frailty.
Conclusions
We found a strong association of NF-kB related inflammation with frailty in PWH. Osteoprotegerin, which may be elevated in PWH and has been linked to frailty in people without HIV, is a TNF-receptor superfamily member that acts as a soluble decoy receptor for receptor activator of NF-kB ligand (RANKL) to inhibit osteoclast formation and prevent bone resorption via the RANKL/RANK pathway. Low proportion of naïve CD4 T cells and increased PD-1 expression was associated with both osteoprotegerin levels and frailty in PWH, suggesting a link between inflammation, T cell activation, bone health, and frailty in PWH.
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