Plasma Proteomic and Metabolomic Predictors of Vascular Disease in Treated HIV

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PROJECT SUMMARY/ABSTRACT People with HIV (PWH) remain at higher risk for Type 1 myocardial infarction (T1MI), ischemic stroke, and venous thromboembolism (VTE) than the general population despite antiretroviral therapy (ART)-mediated viral suppression. Systemic inflammation persists in many PWH despite ART and predicts each of these vascular events, but the optimal interventional targets remain unclear. To begin to address these issues, we performed an initial case-cohort study of nearly 1,200 PWH within the CFAR Network of Integrated Clinical Systems (CNICS) who were maintaining at least 1 year of ART-mediated viral suppression and identified several plasma inflammatory markers – including surrogate markers of microbial translocation, CMV, and the kynurenine pathway of tryptophan catabolism - that predicted increased risk of subsequent vascular events. We also observed that women (particularly at post-menopausal ages) had higher levels of most inflammatory markers than men, and trends suggesting that sex may modify the association between inflammation and vascular events. This proposal will build upon these findings by nearly doubling the adjudicated vascular event cases in our study (n=135 T1MI, n=74 ischemic strokes, and n=135 VTE). We will also assess the plasma proteomic and metabolomic pathways most strongly predictive of each event type and explore the associations between sex and plasma sex hormone levels and the pathways that predict vascular disease. Aim 1 will assess the plasma proteomic pathways that most strongly predict T1MI, ischemic stroke, and VTE using the most comprehensive plasma proteomic platform (SomaScan, targeting 7,000 proteins), and validating the top hits with commercial ELISAs and by cross-validation in the VACS BC cohort. Aim 2 will assess the plasma metabolomic predictors of these vascular events using an untargeted metabolomic approach, confirming top hits with quantitative assays, and quantitative assessments of metabolites previously linked to vascular disease (e.g., kynurenine and carnitine metabolic pathways). For both Aims 1 and 2, we will assess whether the top immunologic hits that predict vascular disease outcomes are also increased in treated HIV compared to HIV-uninfected controls matched for demographics and health-related behaviors in the SCOPE cohort. Aim 3 will assess the degree to which sex and plasma sex hormone levels are associated with the immunologic pathways that predict vascular disease and whether these pathways vary by menopausal status and between transgender women on gender-affirming hormonal therapy and cis-men. Lastly, we will explore whether sex modifies the relationship between inflammatory pathways and vascular disease. These studies leverage a multidisciplinary team with expertise in translational immunology, HIV pathogenesis, vascular disease, metabolomics, epidemiology, and bioinformatics and will create a resource that can be leveraged by others to assess predictors of other disease outcomes and/or add additional analytes. Collectively, these studies will accelerate the identification of novel interventional targets to reduce multi-morbidity in treated HIV infection.