We have assembled a cross-disciplinary collaborative team with global expertise in SARS-CoV-2 virology, viral immunity, RNA virus persistence, cutting edge tissue-based viral assays, animal models of COVID-19, cohort methodology, infectious diseases diagnostics, high-dimensional single cell data analysis, and sex-based differences in respiratory viral infection. Our team includes the primary investigators of an NIH-funded COVID-19 Serology Center of Excellence and four large COVID-19 clinical studies with > 1500 enrolled participants and longitudinal blood and respiratory mucosal sampling coupled with symptom surveys from 2 days after symptom onset through 18 months after symptom onset. We will study the intersection of persistent viral antigen or RNA, host immune response, sex, obesity, and post-acute sequelae of COVID-19 (PASC). Our central hypothesis is that distinct and persistent immune metabolic profiles are associated with specific post-COVID conditions. Through the experiments outlined in this proposal, we will address whether some form of SARS-CoV-2 persistence contributes to PASC or if PASC is entirely a consequence of a remote virus infection, a question with enormous clinical implications.