Vikhyath Jonnalagadda

Background: Little is known about the specific inflammatory networks and immune parameters that drive frailty outcomes in people with HIV (PWH). Methods: Plasma analytes and T-cell phenotypes from PWH without frailty (0 Fried score, n = 60) and with frailty (≥3 Fried score, n = 60) were measured by Luminex assay or flow cytometry. Multiple least-squares linear regression analysis was used to determine the association of each marker with frailty in unadjusted and adjusted models. Spearman correlations were used to determine the association of plasma analytes with T-cell phenotypes. Results: We found that 19 of 75 markers measured in plasma were significantly associated with frailty, most of which are downstream of NF-κB signaling and are senescence-associated secretory phenotype (SASP) components. In frail individuals, the proportions of CD4 and CD8 T cells with a naïve phenotype were significantly reduced, and the proportions of CD4 T cells expressing TIGIT and PD-1 were significantly elevated. Of the frailty-associated analytes, we found that only osteoprotegerin and TNF levels were significantly correlated with percent naïve, TIGIT+, and PD-1+ CD4 T cells among PWH with frailty. Osteoprotegerin levels were negatively correlated with CD4/CD8 T-cell ratio. Conclusions: We found a strong association of the SASP and NF-κB-related inflammation with frailty in PWH. Osteoprotegerin can inhibit osteoclast formation and prevent bone resorption. Low proportion of naïve CD4 T cells and increased TIGIT and PD-1 expression were associated with both osteoprotegerin levels and frailty, suggesting a link between inflammation, T-cell activation, bone health, and frailty in PWH.