Investigating fitness tradeoffs in influenza virus attachment and antibody neutralization
Biophysical Journal(2023)
Abstract
Influenza A virus (IAV) and other respiratory viruses cause seasonal epidemics and occasional pandemics with global mortality in the hundreds of thousands to millions each year. Influenza virions are covered with a dense arrangement of the spike proteins hemagglutinin (HA) and neuraminidase (NA). The high surface density of HA plays a critical role during infection: although interactions between a single HA and its receptor lasts for only ∼1 second, hundreds of concurrent interactions are able to stabilize viral attachment. However, high HA densities also facilitate the binding of multi-valent antibodies that depend on avidity for virus neutralization. Although these types of antibodies are a common element of the immune response to influenza, the tradeoffs between receptor binding and antibody neutralization for virions that present variable densities of HA on their surface remains unclear. Understanding these tradeoffs is particularly important for viruses like influenza that vary considerably in their size, shape, and molecular composition. To address these questions, we developed a fluorescence-based assay for measuring antibody binding kinetics to individual virions. This assay allows us to characterize the binding of antibodies to viral antigens as presented on their native viral surface. Using this assay, we investigate the binding of antibodies that interact with HA with low (monovalent) affinity but high (bivalent) avidity. Additionally, by introducing decoy HAs that are inert to both antibodies and viral receptors, we can tune the density of functional HA on the virion surface and measure its effects on viral fitness in the presence or absence of antibody challenge. Combined with stochastic simulations of bivalent antibody binding, our results indicate that the high surface density of HAs offers diminishing returns for viral fitness in the presence of antibodies that depend on avidity for effective virus neutralization.
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Key words
influenza virus attachment,fitness tradeoffs
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