Phenotypic size heterogeneity is a viral mechanism of persistence

Assembly of many enveloped animal viruses yields a mixture of particle morphologies, from small, essentially isometric forms to vastly longer, filamentous forms. Selective advantage of pleomorphic virus structure is apparent only in vivo, hindering functional characterization of distinct particle shapes. Here we sought to mimic the in vivo pressures on virus entry in cultured cells and in single-particle experiments of membrane fusion for influenza virus preparations enriched in spherical or filamentous particles. We show that filamentous shape confers functional advantage in the presence of neutralizing antibodies or fusion inhibitors and in cases of only limited fusion-protein activation. For very long particles, inactivation of >95% of associated fusion proteins still permits enough active-protein cooperation to induce membrane merger. Experiments with Ebola virus-like particles show that resistance to antibody pressure is a conserved feature of filamentous particles. Our results offer a strategy for averting drug resistance or immune evasion by targeting filamentous virus particles.