Project Summary Despite dramatic improvements in life expectancy with modern antiretroviral therapy (ART), HIV-infected individuals remain at higher risk than the general population for many morbidities including type 2 diabetes mellitus (T2DM). While this increased risk appears to be associated with persistent systemic inflammation despite suppressive ART in preliminary studies, the specific immunologic pathways mediating this effect remain unclear. The long-term goal of this proposal is to determine the immunologic signatures that predict progressive insulin resistance in treated HIV infection. There is now compelling evidence to indicate that T2DM pathogenesis in the general population is spurred on by age-related chronic low-grade inflammation in the white adipose tissue (WAT) that is driven by resident macrophages, particularly in the context of obesity. Interestingly, a redistribution of WAT stores within the body and an increase in visceral adiposity is seen in HIV-infected people where viral suppression has been maintained by antiretroviral therapy (ART), and several indicators highlight that a form of chronic inflammation potentially analogous to that seen in obesity is also brought on by immunological reconstitution in the setting of chronic HIV, even in non-obese individuals. Leveraging an exceptionally well characterized longitudinal cohort of HIV-infected participants (SCOPE), the objective of this proposal is to use systemic, adipose tissue-specific, and cutting-edge radiographic imaging tools to identify tissue-specific, cellular, and molecular biomarkers of progressive glucose dysregulation, with a particular focus on pro-inflammatory myeloid cell subpopulations. The aim is to find immunologic signatures that are strongly associated with incident T2DM and that also predict worsening glucose control over time. The impact of this proposal lies in its potential to identify specific immunologic pathways that mediate the increased risk of T2DM in treated HIV infection to identify targets for novel interventions.