Low-Fidelity Assembly of Influenza A Virus Promotes Escape from Host Cells

Influenza viruses inhabit a wide range of host environments using a limited repertoire of protein components. Unlike viruses with stereotyped shapes, influenza produces virions with significant morphological variability even within clonal populations. Whether this tendency to form pleiomorphic virions is coupled to compositional heterogeneity and whether it affects replicative fitness remains unclear. Here, we address these questions by developing a strain of influenza A virus amenable to rapid compositional characterization through quantitative, site-specific labeling of viral proteins. Using this strain, we find that influenza A produces virions with broad variations in size and composition from even single infected cells. This phenotypic variability contributes to virus survival during environmental challenges, including exposure to antivirals. Complementing genetic adaptations that act over larger populations and longer times, this “low-fidelity” assembly of influenza A virus allows small populations to survive environments that fluctuate over individual replication cycles. [Display omitted] •Influenza A virus forms morphologically and compositionally heterogeneous progeny•Heterogeneity is encoded in assembly and can depend on the growth environment•Progeny of individual virions are as variable as the progeny of large populations•Phenotypic variability helps subsets of the population to escape NA inhibitors Live imaging of influenza A viral particles demonstrates that virion protein composition and morphology varies widely within the population produced by a single infected cell, suggesting that stochastic viral assembly may mediate phenotypic diversity and viral adaptation.