Abstract
The population of influenza virus consists of a huge variety of variants, called quasispecies, due to error-prone replication. Previously, we reported that progeny virions of influenza virus become infected to adjacent cells via cell-to-cell transmission pathway in the presence of oseltamivir. During cell-to-cell transmission, viruses become infected to adjacent cells at high multiplicity since progeny virions are enriched on plasma membrane between infected cells and their adjacent cells. Co-infection with viral variants may rescue recessive mutations with each other. Thus, it is assumed that the cell-to-cell transmission causes expansion of virus quasispecies. Here, we have demonstrated that temperature-sensitive mutations remain in progeny viruses even at non-permissive temperature by co-infection in the presence of oseltamivir. This is possibly due to a multiplex infection through the cell-to-cell transmission by the addition of oseltamivir. Further, by the addition of oseltamivir, the number of missense mutation introduced by error-prone replication in segment 8 encoding NS1 was increased in a passage-dependent manner. The number of missense mutation in segment 5 encoding NP was not changed significantly, whereas silent mutation was increased. Taken together, we propose that oseltamivir expands influenza virus quasispecies via cell-to-cell transmission, and may facilitate the viral evolution and adaptation.
Highlights
The population of influenza virus consists of a huge variety of variants, called quasispecies, due to error-prone replication
During cell-to-cell transmission, viruses become infected to adjacent cells at high multiplicity since progeny virions are enriched on plasma membrane between infected cells and their adjacent cells
Since progeny virions are enriched on the plasma membrane of an www.nature.com/scientificreports infected cell in the presence of oseltamivir, it is assumed that viruses become infected to adjacent cells at high multiplicity of infection via cell-to-cell transmission
Summary
The population of influenza virus consists of a huge variety of variants, called quasispecies, due to error-prone replication. We reported that progeny virions of influenza virus become infected to adjacent cells via cell-to-cell transmission pathway in the presence of oseltamivir. We have demonstrated that temperature-sensitive mutations remain in progeny viruses even at non-permissive temperature by co-infection in the presence of oseltamivir This is possibly due to a multiplex infection through the cell-to-cell transmission by the addition of oseltamivir. Since progeny virions are enriched on the plasma membrane of an www.nature.com/scientificreports infected cell in the presence of oseltamivir, it is assumed that viruses become infected to adjacent cells at high multiplicity of infection via cell-to-cell transmission. We showed that temperature-sensitive (ts) mutations remain in progeny viruses even at non-permissive temperature by co-infection in the presence of oseltamivir We propose that oseltamivir expands the virus quasispecies via cell-to-cell transmission, and cell-to-cell transmission may contribute to the evolution of influenza virus
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