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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.

BACKGROUND Among ART-treated people with HIV (PWH), persistent systemic immune activation contributes to atherogenesis, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH. METHODS Leveraging baseline REPRIEVE data, we interrogated factors associated with soluble CD14 (sCD14) and oxidized LDL (oxLDL). RESULTS The primary analysis cohort included 4,907 from 5 Global-Burden-of-Disease regions (38% female; 48% Black; median age 50y). When levels of sCD14 and oxLDL were characterized by sex, age, and region, female sex and residence in South Asia or Sub-Saharan Africa were associated with higher sCD14 levels while residence in high-income regions was associated with higher oxLDL levels. In fully adjusted models for sCD14, female sex and white race (among those in high-income regions) were associated with higher sCD14 levels while higher BMI and current use of NRTI+INSTI ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, white race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a sub-analysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels. CONCLUSIONS Factors associated with oxLDL and sCD14, two key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (e.g. statins) and behavioral modifications influence sCD14/oxLDL and the extent to which dampening of these markers mediates CVD-protective effects.