Program Summary While we have learned a tremendous amount about human immune responses in recent years, many studies of human immunology examine the system in a static state of health or disease. However, to truly define how a complex system works, dissect the components that interact with each other under dynamic conditions, and gain actionable knowledge of how the system effectively resets (or not) during and after disease, the system must be perturbed. Thus, the central theme of this Program is that by capturing perturbations of the human immune system and performing high resolution studies of key immune cell types and immune reactions in flux we will gain new mechanistic insights into the functional connections driving productive or pathological immune responses in humans. To address this central theme, we propose 3 Projects to: 1) test the hypothesis that post acute sequelae of COVID-19 (PASC) is associated with incomplete clearance of SARS- CoV-2 and/or reactivation of latent viruses, resulting in chronic inflammation and durable immune dysregulation; 2) utilize chronic and cured HCV infection as a human model system for defining the impact of both natural and precision immune perturbation on overall host fitness and health; and 3) define mechanisms of human vaccine- induced immune memory using precision immune perturbation through PD-1 pathway blockade. Each Project captures a key immune perturbation with a major common feature of known timing and nature of the perturbation including viral infection leading to PASC (Project 1), viral cure in a long-standing chronic infection (Project 2), and vaccination in the context of precision disruption of a single immune pathway, PD-1 (Project 3). As a result, we “capture the human experiment” through focused profiling of the human immune system around these key perturbations. These Projects are supported by an administrative Core and two scientific Cores that enable robust human cohort development, management and sample collection (Core B) and high dimensional, highly standardized, large scale and integrated immune landscape profiling for all patients and subjects studied (Core C). This latter effort will allow common themes, immunotypes and cross-disease immune mechanisms to be identified and leverages the interactions across our interconnected Projects. Thus, this highly interactive IPSG CCHI U19 Program will allow us to make major mechanistic advances in our understanding of human antiviral immunity.