Antibodies to influenza A virus hemagglutinin and neuraminidase limit egress and alter the physical properties of released virus particles

Influenza A virus (IAV)-specific antibodies neutralize mature virions by inhibiting functional sites or, in some cases, by promoting virion aggregation. Many antibodies also act on infected cells to reduce virion yields, but the underlying mechanisms and effects on the physical properties and function of released virus particles remain incompletely characterized. Here we use flow virometry to acquire high-sensitivity yield and size measurements of virus particles released in the presence of antibodies. Combined with digital-droplet PCR and electron microscopy, this approach enables comprehensive characterization of antibody-induced changes in particle genome-content and morphology. We show that antibodies rapidly and dynamically alter released particle distributions, reducing yields and inducing the production of larger particles. Both effects result in part from aggregation induced by crosslinking of viral antigen on the infected-cell surface and inhibition of viral NA. However, yield reduction is not fully explained by aggregation, and a subset of induced larger particles are elongated virions. Finally, particles formed in the presence of HA stem-binding antibody, which does not inhibit attachment of mature virions, show reduced attachment in subsequent rounds of infection. Altogether, we uncover an unappreciated mechanism by which antibodies interfere with viral infection that occurs only during budding and release. Our work highlights the necessity of studying how the immune response shapes virus populations in the context of active infection processes.