Intracellular ISG-virus interactions determine viral infection severity and persistence

In innate immune response, type I interferons (IFNs) activate interferon-stimulated genes (ISGs), which suppress viral replication and secretion at the intracellular level. Yet, how these ISG-virus interactions shape infection progression and severity remains poorly understood. Here, we introduce a new viral infection model that explicitly incorporates intracellular ISG-virus dynamics. It structures, for the first time, infected cells based on viral load and ISG expression which offers a computationally efficient and adaptable approach to integrating ISG-virus intracellular dynamics into viral kinetics frameworks. We validate this new approach using patient data for pre-alpha COVID-19 strain and an HIV, then we use it to study the impact of ISG-virus kinetics on viral infection severity and persistence. Our simulations reveal that increased ISG induction prolongs infection by suppressing type I IFN production in infected cells and preventing tissue cell depletion. We further show that effective ISG-mediated viral suppression is critical for controlling infection severity. Finally, the model predicts that moderate viral secretion optimizes viral load production. Overall, the developed framework offers a flexible and computationally efficient tool for exploring the impact of intracellular type I interferon signaling on viral infections. It can be easily adapted to specific diseases and extended with pharmacokinetics-pharmacodynamics models to identify key therapeutic targets for drug development. © 2025 Elsevier B.V., All rights reserved.