Concepts of RNA virus evolution for the design of better antiviral countermeasures.

This century, global human health has been marked by a seemingly increasing list of outbreaks and epidemics caused by RNA viruses - masters of rapid evolution, host switching and immune escape. With a propensity for mutation, coupled with recombination, reassortment and extensive population interactions, RNA viruses generate remarkable genetic diversity within constrained evolutionary landscapes. Although most mutations are deleterious, a subset fuels adaptation to selective pressures and environments, potentially enabling pathogens to reach new hosts and become epidemic and pandemic threats. Recent advances in molecular virology have clarified how mutation biases, genome organization, epistasis and host factors shape viral diversity, revealing both vulnerabilities and evolutionary constraints. These mechanisms underlying viral evolution are now being leveraged to design evolution-informed countermeasures. These include live-attenuated vaccines with reduced risk of reversion, antivirals that target mutationally constrained regions or drive populations towards extinction, or universal vaccines directed against conserved regions. Looking forward, the integration of high-throughput mutational mapping, structural biology and computational modelling, including artificial intelligence-driven predictive tools, promises to transform our ability to anticipate viral evolutionary trajectories. This Review discusses how embedding evolutionary principles into translational virology may improve preparedness for future outbreaks by shifting the field from reactive to predictive strategies.