Proteomic Profile after Intervention with Eplerenone among Persons with HIV

Background Persons with HIV(PWH) well-treated on antiretrovirals have increased arterial inflammation which can lead to development of atherosclerotic disease. We have previously shown that treatment with eplerenone can significantly reduce arterial inflammation, as measured by target to background ratio(TBR) on cardiac 18F-FDG-PET/CT, among PWH. The mechanisms by which eplerenone may have treatment effects remain unclear. Methods We performed a targeted discovery-based approach to identify a proteomics signature associated with eplerenone treatment that may provide a plausible mechanism for the reduction in arterial inflammation. In an exploratory study, we leveraged analyzable samples from participants who completed the 12-month, placebo-controlled, randomized controlled trial MIRABELLA HIV to evaluate 276 proteins(Olink Target 96 Cardiometabolic, Cardiovascular II, Cardiovascular III), with relevance to cardiovascular and cardiometabolic disease. Results We identified 11 proteins that differed in expression between treatment groups. Eight proteins(CDH1, CES1, ADM, IL-4RA, FGF-21, FS, FABP2, Gal-4) decreased and two proteins increased(CSTB, MPO) in expression with eplerenone compared to placebo. An increase in expression of IL-27 was prevented among eplerenone-treated vs. placebo-treated groups. Changes in TBR of the most diseased segment of the index vessel correlated with changes in three of these proteins:CDH1(ρ=.53, P=.02), FGF-21(ρ=.64, P=.003) and Gal-4(ρ=.58, P=.009). Conclusion Through this proteomics approach, we discovered three key proteins, CDH1, FGF-21, and Gal-4, are decreased in parallel with reductions in arterial inflammation after treatment with eplerenone. Eplerenone-induced reductions in these proteins, known to be related to inflammation, epithelial barrier disruption, vascular dysfunction and metabolic dysregulation, provides mechanistic insight into pathways by which eplerenone may improve CVD in HIV.