CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Results: As expected, we detected HIV in aorta from all donors with HIV and not in those without HIV. Using spatial transcriptomics, several genes were differentially expressed by HIV status. Apolipoprotein D (APOD), a lipocalin associated with premature atherosclerosis and poor outcomes in persons with coronary artery disease was significantly higher in the aorta of all donors with HIV (n=4). Osteoglycin (OGN), a gene linked with vascular calcification, was higher in donors without HIV (Panel A). Both genes were expressed mainly by fibroblasts while APOD was also expressed in endothelial cell clusters. Metabolomic analysis of the aorta also showed differential expression of different metabolites (Panel B) with higher Linoleic acid in all three aorta samples from donors with HIV compared to donors without HIV. Conclusion: APOD has been associated with poor outcomes in coronary artery disease, and may be a therapeutic target in persons with HIV. A comprehensive multimodal approach to investigating atherosclerotic cardiovascular disease in HIV is likely to provide new therapeutic targets.

crosstalk between vascular and immune cells that may underly, in part, the increased risk of cardiometabolic conditions linked to chronic inflammation.

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Elevated Triglycerides and Endothelial Vasodilator Dysfunction in Adults Living With HIV-1 Vinicius P Garcia 1 , Kelly A. Stockelman 1 , Anthony R. Bain 1 , Cynthia Firnhaber 1 , Jared J. Greiner 1 , Brian L. Stauffer 1 , Elizabeth Connick 2 , Christopher DeSouza 1 1 University of Colorado Boulder, Boulder, CO, USA, 2 University of Arizona, Tucson, AZ, USA Background: Adults living with HIV (ALWH) commonly have high triglyceride (TG) levels contributing to their increased risk of cardiovascular disease (CVD). Indeed, elevated TG levels are independently associated with an increased risk of myocardial infarction in ALWH. A major underlying mechanism for the TG related increase in CVD is a profound worsening in vascular endothelial function. The influence of high TG levels on vascular endothelial function in ALWH is unknown. We tested the hypotheses that: 1) high TG levels are associated with worse endothelium-dependent vasodilation in antiretroviral (ART)-treated ALWH; and 2) the TG-related reduction in endothelial vasodilator function is due, in part, to diminished nitric oxide (NO) bioavailability. Methods: Forty-two sedentary, non-obese, normotensive, non-medicated (aside from ART) middle-aged men were studied: 14 healthy adults (age: 38+3 yr; TG: 73+8 mg/dL); 14 ALWH on stable antiretroviral therapy with normal TG (42+2 yr; 98+7 mg/dL); and 14 ALWH on stable antiretroviral therapy with elevated TG (43+2 yr; 234+17 mg/dL). Aside from TGs all other lipid and lipoproteins, glucose and insulin levels were clinically normal. Forearm blood flow (FBF) responses to intra-arterial infusion of the endothelial agonist acetylcholine (Ach), in the absence and presence of the endothelial NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), as well as the endothelium independent vasodilator sodium nitroprusside were determined by venous occlusion plethysmography. Results: FBF responses to Ach were significantly lower (~20%) in the ALWH with normal TG (from 4.5±0.3 to 13.1±0.7 mL/100 mL tissue/min) vs healthy adults (4.9±0.3 to 17.3±0.7 mL/100 mL tissue/min); whereas, the ALWH with high TG (4.3±0.3 to 10.2±1.0 mL/100 mL tissue/min) demonstrated FBF responses to Ach significantly lower than ALWH with normal TG and healthy adults. L-NMMA significantly reduced the FBF response to Ach in the healthy (~30%) and ALWH with normal TG (~25%) but not the ALWH with high TG (~10%). There were no significant group differences in the FBF response to sodium nitroprusside. TG levels were inversely and significantly associated with the FBF response to Ach (r=-0.51; P=0.005) in the ALWH. Conclusion: Elevated TG levels is associated with lower endothelium dependent vasodilation in adults living HIV-1 due, in part, to reduced NO bioavailability. Diminished NO-mediated endothelium-dependent vasodilation may underlie the increased risk of CVD in ALWH with high TG levels. Spatial Profiling Reveals Immunometabolic Pathways Involved in Trained Immunity in PWH With CVD Cheryl Cameron 1 , Emily Bowman 2 , Leah Zagore 1 , Banumathi Tamilselvan 1 , Brian Richardson 1 , Thura Harfi 2 , Susan L. Koletar 2 , Jon Lomasney 3 , Michael L. Freeman 1 , Joseph Willis 1 , Elizabeth Mayne 4 , Michael M. Lederman 1 , Matthew J. Feinstein 3 , Nicholas Funderburg 2 , Mark Cameron 1 1 Case Western Reserve University, Cleveland, OH, USA, 2 The Ohio State University, Columbus, OH, USA, 3 Northwestern University, Chicago, IL, USA, 4 University of Cape Town, Cape Town, South Africa Background: People with HIV (PWH) are at increased risk for cardiovascular disease (CVD). Chronic exposure of innate immune cells to microbial products and pro-inflammatory lipids may drive trained immunity in these cells through transcriptomic and metabolism changes. Methods: We measured coronary artery calcium (CAC) scores among people with and without HIV (N=25,43) to assess atherosclerosis and vascular age. Blood was collected from participants for assay of serum markers of immune

Poster Abstracts

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Endothelial Dysfunction in HIV: Exploring Cytokine and Chemokine Dynamics Celestine Wanjalla , Joey Stolze, Samuel Bailin, Mona Mashayekhi, Sheng Quanhu, Curtis L. Gabriel, Xiuqi Zhang, David G. Harrison, John Koethe Vanderbilt University, Nashville, TN, USA Background: In persons living with HIV (PWH), chronic inflammation promotes endothelial dysfunction, which contributes to cardiovascular disease. In this study, we sought to understand how subsets of endothelial cells (ECs) in adipose tissue modulate inflammation. Methods: We analyzed the expression of cytokine/chemokine receptors by ECs in the subcutaneous adipose tissue of 59 PWH using single-cell RNA sequencing. We analyzed the association of EC subsets within adipose tissue with plasma cytokines and computed tomography morphometric measures. CellChat analysis was used to identify potential interactions between ECs and immune cells to further define the role of cytokines/chemokines. We also performed bulk RNA sequencing of human arterial ECs cultured in media conditioned with plasma from PWH to assess the direct effects of cytokines. Results: The pattern of cytokine and chemokine receptor expression was different in the various subcutaneous adipose cell types identified: including capillary, venous, and arterial ECs; pericytes and vascular smooth muscle cells. Venous ECs expressed the il6r and the proportion of venous ECs was positively correlated with triglycerides (ρ=0.43, p=0.04), visceral fat volume (ρ=0.29, p=0.02), and plasma IL-6 (ρ=0.35, p<0.01), and negatively correlated with liver density (ρ=-0.32, p=0.01). Capillary ECs had relatively low levels of il6r compared to venous endothelial cells and were positively correlated with the mean liver density (ρ=0.36, p<0.01) and negatively with visceral fat volume (ρ=-0.34, p=0.01), and plasma IL-6 (ρ=-0.29, p=0.01). Analysis of intercellular communication between ECs and immune cells shows that capillary ECs have the potential to secrete chemokines that signal directly to venous endothelial cells, and this is mediated by classical and non-classical monocytes (Figure A). Arterial ECs cultured with plasma from PWH when compared to media controls differentially expressed genes that enriched for the TNF-α pathway via NFκB, and reactive oxygen species pathway (Figure B). Conclusion: Cytokine and chemokine signaling between subcutaneous adipose tissue arterial, capillary and venous endothelial cells is potentially mediated by classical and non-classical monocytes. In PWH, this may indicate a dynamic

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CROI 2024 233