PROJECT SUMMARY: People with HIV (PWH) experience a heightened risk of atherosclerotic cardiovascular disease (ASCVD) that is attributed, in part, to chronic inflammation. Lipoprotein(a) (Lp[a]), a non-traditional ASCVD risk factor is the major carrier of oxidized phospholipids, which are increased in pro-inflammatory states and which damage vascular cells at the vessel//lumen interface. Identifying Lp(a) risk thresholds, the increment in ASCVD risk for a given increment in Lp(a), would improve risk prediction and inform entry criteria and treatment goals for future Lp(a) lowering therapies in PWH. Our project defines Lp(a) risk thresholds in PWH, explores two possible responsible mechanisms for Lp(a) risk in PWH, and studies regulation of hepatic Lp(a) production in PWH through the inflammatory cytokine IL-6 signaling pathway using sera from PWH. The study results will address critical knowledge gaps and test specific hypotheses related to the Lp(a) associated heightened ASCVD risk in PWH. Aim One utilizes serial coronary and carotid studies of subclinical ASCVD in the MACS/WIHS Combined Cohort Study (MWCCS) cohorts and biospecimens to establish Lp(a)-specific ASCVD risk thresholds in PWH. We will also explore racial disparities as Lp(a) levels in healthy Black people are higher than in healthy White people. Aim Two explores two mechanisms that may explain an association between Lp(a) and the HIV-specific heightened ASCVD risk. The first examines whether Lp(a) is associated with impaired coronary endothelial vascular function, a driver of ASCVD. It uses non-invasive MRI to assess endothelial-dependent coronary function in newly recruited PWH and PWoH. The second measures the association of Lp(a) with coronary vascular inflammation, another driver of ASCVD pathogenesis, using the validated fat attenuation index developed at Oxford University to measure coronary inflammation from MWCCS coronary CT scans. Aim Three examines regulation of Lp(a) production in PWH, a poorly understood aspect of ASCVD risk in PWH. Our preliminary in vitro cell data suggest that the inflammatory cytokine IL-6, known to be elevated in PWH and associated with ASCVD, enhances hepatocyte LPA transcriptional activity via the JAK-STAT pathway. Moreover, the genetic variant rs56393506, known to amplify Lp(a) production, will be studied. We will utilize induced pluripotent stem cell-derived hepatocytes exposed to sera from PWH to examine IL-6 signaling pathways of hepatic Lp(a) production. Additionally, we will utilize the exisitng MWCCS genomics dataset to assess whether known variants linked to Lp(a) identified in published GWAS are associated with the higher Lp(a) levels in PWH. In summary, this comprehensive research identifies Lp(a)-specific ASCVD risk thresholds in PWH by leveraging data from the MWCCS cohorts, studies two mechanisms that may explain why Lp(a) is associated with this risk, as well as pathways of hepatic regulation of Lp(a) production in PWH. We expect the...