PROJECT SUMMARY/ABSTRACT Our long-term goal is to identify bioactive lipid metabolites that are dysregulated in HIV-infected individuals and to gain a fundamental understanding of these lipid metabolites in liver disease pathogenesis and the development of liver-related complications. The overall objective is to utilize HIV/HCV-coinfection as a model to probe for underlying mechanisms of accelerated liver fibrosis and disease progression with the overall premise that there is a common final pathway of liver injury that is metabolic in nature. Our central hypothesis is that dysregulation of bioactive lipid metabolism reports on a common mechanism by which HIV-infection, antiretrovirals, and viral co-infections interact to modulate fibrogenesis. Based on evidence that HCV dramatically modulates host cell lipid metabolism and HIV-infection and antiretrovirals also perturb lipid pathways, we propose that accelerated fibrogenesis in HIV is due, at least in part, to additive hits on lipid metabolism and excess accumulation of detrimental lipid metabolites, like ceramide. Thus, we used a multi-targeted lipidomics platform to investigate bioactive lipids as predictors of liver fibrosis stage. Our preliminary studies indicate that (1) expression of bioactive lipids correlates with histopathologic stage of liver disease in patients with HIV/HCV and HCV infections, and (2) clearance of HCV using DAA regimens results in rapid changes in lipid homeostasis pathways. The proposed work will test our hypothesis that dysregulation of bioactive lipid metabolism in HIV- infection plays a key role in progressive liver disease, as well as the corollary hypothesis that variations in lipid expression can be used as noninvasive assessments of liver disease complications. We will accomplish the objective of the application by pursuing the following Specific Aims: (1) Discover and validate specific expression patterns of circulating bioactive lipid metabolites that are predictive of end-stage liver disease complications in patients with HIV/HCV-coinfection;; (2) Determine unique patterns of circulating bioactive lipid metabolite expression for patients with HIV-infection including those with and without HCV co-infection and non-virally mediated metabolic liver disease (NAFLD/NASH);; (3) Identify specific bioactive lipid metabolite expression that is modified by DAA treatment-induced HCV clearance and statin initiation in HIV/HCV co-infected patients. The impact of this proposal will be to fundamentally change our understanding of the metabolic mechanisms of liver disease in people living with HIV. We will develop a novel, noninvasive assessment of end-stage liver disease complications that will have immediate clinical utility. We will also apply this validated, noninvasive metabolite profile as a to...