Environmental stochasticity can account for patterns of within-host respiratory virus evolution

The ecological and evolutionary dynamics of populations, including viral populations, are known to be jointly shaped by deterministic and stochastic processes. While the impact of stochastic processes has been rigorously explored for viral dynamics at the level of the host population, most dynamic models for acutely-infecting respiratory viral pathogens at the within-host scale remain deterministic in their formulation. While this may be reasonable for identifying key processes shaping their within-host viral population dynamics, recent studies indicate that stochastic processes need to be invoked for understanding patterns of within-host viral evolution. Specifically, several studies have shown that viral allele frequencies can change dramatically over the time course of days in acute infections. Here, we use stochastic dynamic models to explore the role of environmental noise in shaping observed patterns of virus evolution in acute respiratory virus infections. We summarize ways in which environmental stochasticity can be biologically realized in these acute viral infections and describe within-host models that can be implemented to jointly yield viral population dynamics and evolutionary dynamics. We further develop a statistical approach to estimate the extent of environmental noise from observed within-host allele frequency changes. We test this approach on simulated data and apply it to existing influenza A virus and SARS-CoV-2 within-host data. With these applications, we show that environmental stochasticity can parsimoniously reproduce key features of empirically observed allele frequency changes without needing to invoke demographic stochasticity or to adopt Wright-Fisher model formulations with a constant effective population size. Finally, we show that purifying selection and positive selection can both still contribute to within-host viral evolution in the context of a noisy environment, providing theoretical support for studies that have found purifying and positive selection in acutely-infecting respiratory virus populations.