Friday, May 9, 2025
5/9/2025
The study of Eicosanoids as Novel Inflammatory Mediators of CVD in Men and Women with HIV - Advances in antiretroviral therapies (ART) have greatly improved the survival of people with human immunodeficiency virus (HIV) infection (PWH); yet, the leading cause of death in PWH across all ages is now cardiovascular disease (CVD). While the pathogenesis of HIV-associated CVD is thought to be multifactorial resulting from the interplay of traditional CVD risk factors, exposure to ART, chronic inflammation, and immune activation that persists despite viral suppression; a comprehensive mechanistic framework is lacking to provide further insights into the etiology of CVD in PWH. Importantly, the “female advantage” for CVD risk is attenuated in the context of HIV, with an increase in MI and stroke risk reported in women when compared to men. Inflammation is recognized as a central driving factor in CVD pathogenesis irrespective of HIV status but is more pronounced in PWH. In a study of ART-suppressed PWH within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, our team identified distinct biomarkers of inflammation that predicted inflammatory related clinical events in a sex-specific manner. However, efficient therapies targeting inflammatory processes are still lacking. Accumulating evidence suggests that the upstream initiation of inflammatory activity is governed by products of polyunsaturated fatty acids (PUFAs) and that eicosanoids, the best-characterized bioactive PUFA derivatives, play a role in CVD pathogenesis by modulating vascular tone, cellular regeneration and thrombosis. The COX pathway involved in eicosanoid production is of particular clinical relevance as it is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), used to treat pain, fever and inflammation. Recent advances in mass spectrometry have allowed our team to quantify hundreds of eicosanoids in the plasma of two non-HIV cohorts and detect specific pathways linked to CVD risk, some in a sex-specific manner. However, the causal role of plasma eicosanoids in CVD pathogenesis in PWH has not been elucidated. Therefore, our objective is to leverage CNICS cohort with adjudicated clinial events to elucidate the role of eicosanoids in CVD risk in PWH. We hypothesize that eicosanoids serve as inflammatory mediators of HIV-associated CVD pathogenesis and explain, at least in part, the sexual dimorphism seen in CVD risk. We propose to 1. Characterize plasma eicosanoid profiles of PWH compared to matched non-HIV controls and establish their relationship with CVD risk factors, HIV related factors (disease duration, viral load, CD4 counts), sex and clinical events among 3,000 PWH; 2. Assess causal inference of eicosanoids on cardiovascular events and identify unique genetic loci associated with eicosanoid profiles in PWH, and 3. Integrate lipidomics, metabolomics, proteomics and genomics data with clinical information to detect novel biological pathways and key drivers of cardiovascular risk in PWH and identify novel or repurposed intervention drug targets. The proposed studies will guide future development of efficacious, potentially sex-stratified, interventions for CVD in individuals with and without HIV.
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