ABSTRACT HIV and antiretroviral therapy (ART) are associated with adipose tissue (AT) dysfunction and systemic metabolic alterations, including intra-abdominal fat accumulation, fatty liver disease, dyslipidemia, and insulin resistance. Treatment of these defects using conventional drugs and lifestyle interventions has been minimally effective. Viral factors and ART contribute to the complex pathophysiology of these disease states in persons living with HIV (PLWH). Still, the mechanisms that link viral factors and ART to defective AT and hepatic metabolism remain incompletely understood. We have demonstrated in mouse models that the HIV accessory protein Vpr is sufficient to cause all the cardinal manifestations of HIV-associated metabolic disease. The Vpr mice also have high levels of FGF21 and increased subcutaneous AT thermogenesis. The current proposal aims to establish mechanistic connections between increased FGF21 levels, white AT thermogenesis, and the observed metabolic abnormalities in Vpr mice and PLWH. Our central hypothesis is that Vpr expression alters the metabolic effects of FGF21, altering AT and hepatic function and inducing maladaptive browning of subcutaneous white AT. We will test this hypothesis by achieving the following Specific Aims: 1) Determine how Vpr exposure affects white AT thermogenesis in mice; 2) Demonstrate how FGF21 shapes the metabolic abnormalities of Vpr mice; 3) Establish relationships between FGF21’s endocrine actions and defects of lipid and glucose metabolism and subcutaneous white AT function in PLWH on suppressive ART. Our research plan will provide detailed dissection of the relationships between HIV-associated metabolic disease and FGF21 physiology, molecular mechanisms of thermogenesis and AT physiology, and immunology. The project will reveal mechanisms of unique metabolic defects in Vpr mouse models that recapitulate those in PLWH, and elucidate how FGF21’s endocrine functions contribute to HIV-associated metabolic abnormalities in PLWH on ART. Ultimately, this translational work will identify mechanisms of HIV-specific metabolic alterations and may identify therapeutic targets that can be exploited to minimize the long-term clinical burden of metabolic disease in PLWH.