Plaque and blood derived macrophages: a multi-omic assessment of CVD pathogenesis in PLWH

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Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death in the United States; and there is ~2-fold greater risk for CVD events for people living with HIV (PLWH).1,2 The mechanisms underlying increased CVD prevalence in PLWH are not fully understood, but likely involve heightened activation of monocytes and macrophages. We hypothesize that monocytes will be exposed to disparate inflammatory signals during differentiation in PLWH; as a result, macrophages will be functionally and phenotypically different and exacerbate CVD in this population. Our data suggest that alterations in the lipidome may influence inflammation, monocyte activation, and the differentiation of macrophages. Antiretroviral therapy may alter lipid profiles by reducing oxidative phosphorylation (OxPHOS) and fatty acid oxidation (FAO) as a consequence of ART-induced mitochondrial dysfunction. Our studies have identified differences in the lipidomes of HIV- and HIV+ populations, even when traditional lipid panels in these groups were similar22. Biomarkers associated with CVD risk (IL-6, sCD14, TNFR1),10-15 were directly related to fatty acid composition and pro-inflammatory lipid classes in PLWH. We have also identified an expansion of pro-coagulant, vascular homing monocytes in PLWH42-44 and linked monocyte activation to altered lipid profiles19,20,45-47. Aim 1: To identify unique and common phenotypic, transcriptomic, and functional MDM profiles associated with the presence or absence of ASCVD in PLWH and HIV- individuals. 1A: To compare MDM phenotypic, functional, and transcriptomic profiles across our 4 groups. 1B: To sort and differentiate monocyte subsets (based on CD14 and CD16 expression)43,49,50 into MDMs in order to determine whether subset origin determines differential functional and phenotypic outcome. 1C: To sort macrophages from atherosclerotic plaques (carotid endarterectomies) and compare the transcriptional profiles of these cells to the profiles identified in MDMs from our 4 participant groups. Aim 2: To characterize drivers of MDM activation in PLWH and HIV- persons with and without ASCVD. 2A: To characterize the plasma lipid profiles of participants using advanced lipidomics (Lipidyzer) as well as the lipidomic profiles of atherosclerotic plaques collected from carotid endarterectomies. 2B: To explore the consequences of in vivo and in vitro lipid profile modulation on MDM gene expression and functional capabilities; statin treatment will improve the lipidome51 and as a consequence, decrease MDM activation, and in vitro exposure of MDMs to proinflammatory lipids (i.e CERs, SaFAs) will activate these cells. 2C: To determine the drug-specific effects of ART exposure on MDM profiles. Aim3: To elucidate profiles associated with ASCVD in HIV- and HIV+ individuals using a comprehensive, multi-dimensional approach and in vitro pathway inhibitor experiments to explore differential drivers and inhibitors of signaling cascades on MDM transcription and functional profiles.