bioRxiv2025
Positive-sense RNA viruses that constitute a large class of human pathogens employ various strategies to suppress and evade host immune defenses. Understanding the dynamic interaction between the viral life cycle and immune signaling is crucial to designing effective antiviral strategies. Although significant progress has been made, quantitative models that can accurately capture the intricate interactions and the intertwined dynamics during viral infection of cells remain missing. In this study, we develop a comprehensive mathematical model that integrates the intracellular viral life cycle with key cellular innate immune pathways, including RIG-I-mediated detection and JAK-STAT signaling. The model provides mechanistic insights into long-standing observations, capturing both virus-specific dynamics and innate immune response, and the key components driving their coupled dynamics. For example, a comparison of viruses shows how the Japanese Encephalitis virus undergoes a dramatic reduction in viral load in cells, due to its rapid replication that robustly activates the RIG-I pathway, in contrast to the poor immune control of HCV. More importantly, our model demonstrates how virus-host interactions exhibit a sharp bifurcation behavior, where minor differences in immune strength or viral suppression capacity can determine whether infections resolve or persist. We propose that ISG mRNA translation and viral replication predominantly dictate these bimodal infection outcomes. Additionally, the model not only recapitulates but also highlights molecular players involved in IFN desensitization. We demonstrate how our models ability to capture IFN dynamics allows us to predict optimal timing and dosing strategies for interferon-based prophylactic therapies. Together, our approach reveals fundamental features that govern the delicate balance between the establishment of infection and immune control in RNA virus infections. Author SummaryViruses responsible for diseases like hepatitis and dengue rapidly proliferate by invading host cells, which in turn activate immune responses to counteract the infection. Viruses have also developed a variety of mechanisms to interfere with this immune response, thereby complicating the process of effectively treating infections. Here, we simulate the comprehensive sequence of molecular-level actions and the corresponding counteractions that occur between the virus and the host cell components as the infection proceeds. We find that the battle between the virus and the immune system behaves like a seesaw, and small changes can dramatically tip the balance. Sometimes, a tiny boost to our immune response or a small weakness in the virus can mean the difference between cells succumbing to infection or recovering completely. Similarly, it is now possible to recognize why specific viruses are more effectively controlled by the immune system compared to others. We can now explain the decline in the immune response to interferon therapy with prolonged use and suggest the optimal timing and dosing for such treatments. For example, we found that interferon treatment administered before infection, even in small doses, can block the virus more effectively than treatment after infection begins. In addition, we propose better ways to inhibit the virus by effectively combining complementary approaches, such as blocking its replication or its ability to hide from the immune system, which can boost the effectiveness of interferon treatment. This work provides a roadmap for developing quantitative and more effective antiviral approaches by understanding the precise biological mechanisms that determine how hosts can overcome virus infection.