Immune pressure is key to understanding observed patterns of respiratory virus evolution in prolonged infections.

Analyses of viral samples from prolonged SARS-CoV-2 infections as well as from prolonged infections with other respiratory viruses have indicated that there are several consistent patterns of evolution observed across these infections. These patterns include accelerated rates of nonsynonymous substitution, viral genetic diversification into distinct lineages, parallel substitutions across infected individuals, and heterogeneity in rates of antigenic evolution. Here, we use within-host model simulations to explore the drivers of these intrahost evolutionary patterns. Our simulations build on a tunably rugged fitness landscape model to first assess the role that mutations that impact only viral replicative fitness have in driving these patterns. We then further incorporate pleiotropic sites that jointly impact replicative fitness and antigenicity to assess the role that immune pressure has on these patterns. Through simulation, we find that the empirically observed patterns of viral evolution in prolonged infections cannot be robustly explained by viral populations evolving on replicative fitness landscapes alone. Instead, we find that immune pressure is needed to consistently reproduce the observed patterns. Moreover, our simulations show that the amount of antigenic change that occurs is higher when immune pressure is stronger and at intermediate immune breadth. While our simulation models were designed to shed light on drivers of viral evolution in prolonged infections with respiratory viruses that generally cause acute infection, their structure can be used to better understand viral evolution in other acutely infecting viruses such as noroviruses that can cause prolonged infection as well as viruses such as HIV that are known to chronically infect.