Abstract
BACKGROUND: Persons with HIV (PWH) on contemporary antiretroviral therapy (ART) are at elevated risk for developing age-related cardiometabolic diseases. We hypothesized that integrative analysis of cross-tissue, multimodal data from PWH could provide insight into molecular programming that defines cardiometabolic phenotypes in this high-risk group. METHODS: We enrolled 93 PWH without diabetes who were virologically suppressed on contemporary ART and obtained measures of insulin resistance, glucose intolerance, and adiposity. We performed circulating lipidomics, proteomics, and metabolomics, as well as subcutaneous adipose tissue (SAT) bulk transcriptomics, and used multiomics factor analysis (MOFA) to perform integrative analyses of these datasets. RESULTS: The median age was 43 years, median body mass index 30.8 kg/m2, 81% were male, and 56% were self-identified non-Hispanic White. We identified a specific MOFA factor associated with visceral adipose tissue volume (ρ = -0.43), homeostasis model assessment 2 insulin resistance score (ρ = -0.52), liver density (ρ = 0.43), and other cardiometabolic risk factors, which explained more variance in the SAT transcriptome and circulating lipidome compared with the circulating proteome and metabolome. Gene set enrichment analysis of this factor showed extracellular matrix and inflammatory pathways that primarily mapped to SAT myeloid cells and adipose progenitor cells using single-cell deconvolution. Lipidomic analysis showed that this factor was significantly enriched for triacylglycerol and diacylglycerol species. CONCLUSIONS: Our multiomic analysis demonstrated coordinated, multitissue molecular reprogramming in virologically suppressed PWH with elevated cardiometabolic disease risk. Longitudinal studies of PWH with assessments of adipose tissue and lipid handling are necessary to understand mechanisms of cardiometabolic disease in PWH. Clinical Trials Registration. NCT04451980.