Cardiovascular disease (CVD) is the 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. Monocytes retained within atherosclerotic plaques are exposed to signals that drive their differentiation into macrophages;3,4 these cells display phenotypes that are more complex than M1/M2 classification5-7. 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. Immune activation persists despite viral suppression by antiretroviral therapy (ART)8,9 and several monocyte-related inflammatory markers (including sCD14, IL-6,TNFR1) predict mortality,10-15 including deaths related to CVD12,15 in PLWH. Multiple factors10,16-18 contribute to immune activation in ART-treated PLWH, including pro-inflammatory lipids.19-22 Our data suggest that alterations in the lipidome may influence 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 dysfunction23-25. Traditional lipid panels are insufficient to assess CVD risk in PLWH26; lipidomics analyses have revealed associations of lipid classes, species, and fatty acid (FA) composition with several diseases, including CVD7,27-36. Some saturated fatty acids (SaFAs) can directly activate monocytes and macrophages37-39 and some polyunsaturated FAs (PUFAs) can inhibit activation of these cells40,41. 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 SaFA composition, and inversely to PUFA composition in both HIV- individuals and PLWH. Our work has also identified an expansion of pro-coagulant, vascular homing monocytes in PLWH42-44 and linked monocyte activation to altered lipid profiles19,20,45-47 We hypothesize that there are unique drivers of myeloid cell activation in PLWH that alter monocyte derived macrophage (MDM) profiles and may exacerbate CVD.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. Hypothesis: MDMs from PLWH will have a more pro-atherosclerotic profile (altered lipid processing, increased innate immune signaling, and matrix metalloproteinase production) compared to MDMs from HIV- individuals, in both people with and without ASCVD based on coronary artery calcification (CAC score of 0=ASCVD-; CAC>100=ASCVD+). CAC score is directly related to CVD risk48 and identifies atherosclerosis. 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 identify drivers of MDM activation in PLWH and HIV- persons wi
|Effective start/end date||9/15/21 → 8/31/25|
- Ohio State University (GR125077|SPC-1000006221 Amnd 2 // 1R01HL158592-01)
- National Heart, Lung, and Blood Institute (GR125077|SPC-1000006221 Amnd 2 // 1R01HL158592-01)
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