ABSTRACT The objective of this supplement application is to investigate targeted kynurenine (KYN) pathway metabolites as molecular mechanisms by which objectively measured habitual sleep and circadian disruption increase risk for HIV-associated cardiometabolic disease and to determine whether these relationships differ by biological sex and HIV disease status. We will measure targeted KYN pathway metabolites in stored plasma (n=800) from well characterized MACS/WIHS Combined Cohort Study (MWCCS) men who already have habitual sleep measures collected, validated, and systematically scored via one week continuous wrist actigraphy (Philips Respironics Actiwatch Spectrum Plus). There will be no MWCCS participant and field staff burden for this supplement. No study to date has examined KYN pathway activation as a mechanism linking sleep and circadian disruption to HIV-related and inflammatory mediated comorbidities such as cardiometabolic disease in a mixed sex sample nor has this been accomplished with representation across all HIV disease status groups (well and poorly controlled HIV with comparison to uninfected controls). Results will provide novel insights into biological sex and HIV disease status differences in the mechanistic relationships between sleep and circadian disruption, KYN pathway activation, and HIV-associated cardiometabolic disease and provide a strong foundation upon which to test targeted sleep and circadian interventions to reduce risk for HIV- associated comorbidities in men and women aging with HIV.