Proteomic Signature of Subclinical Coronary Artery Disease in People With HIV: Analysis of the REPRIEVE Mechanistic Substudy

Abstract

Background People with HIV (PWH) have subclinical coronary artery disease (CAD) despite low traditional atherosclerotic cardiovascular disease (ASCVD) risk scores. Coronary plaque in PWH presents as a unique phenotype, but little is known about the contributions of specific inflammatory pathways to plaque phenotypes in PWH. Methods The REPRIEVE Mechanistic Substudy enrolled PWH on ART without known cardiovascular disease. We used a targeted discovery proteomics approach to evaluate 246 unique proteins representing cardiovascular, inflammatory and immune pathways. Proteomic signatures were determined for presence of coronary artery calcium (CAC > 0) and presence of coronary plaque. Results Data were available for 662 participants [51 ± 6 years, ASCVD risk score 4.9%±3.1%]. Among 12 proteins associated with both CAC and presence of coronary plaque, independent of ASCVD risk score, the ORs were highest for NRP1 [5.1(95% CI 2.3-11.4) for CAC and 2.9(95% CI 1.4-6.1) for presence of plaque]. Proteins uniquely related to presence of plaque were CST3, LTBR, MEPE, PLC, SERPINA5, and TNFSF13B; in contrast, DCN, IL-6RA, OSMR, ST2 and VCAM1 were only related to CAC. Conclusions Distinct immune and inflammatory pathways are differentially associated with subclinical CAD phenotypes among PWH. This comprehensive set of targets should be further investigated to reduce atherosclerosis and ASCVD in PWH.

Associations of inflammation-related proteome with demographic and clinical characteristics of people with HIV in South Africa

“…CCL23, SLAMF1 and MCP-1 are involved in monocyte activation, which could lead to sustained inflammation among PWH 6,12 and were suggested to be involved in the pathogensis of several age-related diseases, such as cardiovascular diseases (CVD) 20 , chronic kidney disease 21 , rheumatoid arthritis and atopic dermatitis 6,22,23 . CCL23 was shown to be positively associated with the presence of coronary plaque among PWH 24 , and genetic variants in the SLAMF1 gene that regulate the abundance of SLAMF1 protein were associated with memory decline 25 . MMP-1 functions primarily to degrade several types of collagens and plays an important role in skin aging 26 .…”

Targeted plasma proteomics reveals upregulation of distinct inflammatory pathways in people living with HIV

“…Previous studies have highlighted the relation of these proteins with the pathophysiology ( Cai et al., 2014 ; Kubin et al., 2011 ) and the incidence of CVD ( Bell et al., 2016 , 2018 ; Bielinski et al., 2017 ; Ferreira et al., 2019 ; Gruson et al., 2017 ; Ikeda et al., 2021 ; Ix Joachim et al., 2012 ; Paul et al., 2021 ; Vázquez-Sánchez et al., 2021 ) in the general population and PLHIV ( Atta et al., 2016 ; Domingo et al., 2015 ; García-Broncano et al., 2014 ). In addition, OSM receptor has been reported to be associated with the presence of coronary calcium, independent from traditional atherosclerotic CVD risk, in PLHIV on ART ( Kolossváry et al., 2022 ). Collectively, these findings support previous reports that increased inflammation may follow or induce non-AIDS comorbidities, and further pinpoint PD-L1, VEGFA, LAP TGFβ-1, and TNFRSF9 as possible targets to decrease the risk for malignancies in well-treated PLHIV.…”

Ideal cardiovascular health, biomarkers, and coronary artery disease in persons with HIV

“…Numerous studies have noted altered immune activation and inflammatory indices in PWH; the excess in CV events has been attributed to this alternative mechanistic pathway independent of traditional risk factors [20,39].…”

“…Numerous studies have noted altered immune activation and inflammatory indices in PWH; the excess in CV events has been attributed to this alternative mechanistic pathway independent of traditional risk factors [ 20 , 39 ]. As with the relationships noted between CVH and events and atherosclerosis, two studies in the general population have also found relationships between poor CVH and a variety of biomarkers including higher PAI-1, aldosterone, hs-CRP, D-dimer, fibrinogen, homocysteine, GDF-15, hs-troponin T, IL-6 and GlycA, and lower levels of NT-proBNP [ 8 , 14 ].…”