title: Oseltamivir expands quasispecies of influenza virus through cell-to-cell transmission.
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.
authors.affiliation: Department of Infection Biology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Infection Biology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Murano
authors.affiliation: Division of Biomedical Science, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ryosuke L
authors.initials: RL
authors.lastname: Ohniwa
authors.affiliation: Department of Infection Biology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawaguchi
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001692:Biological Transport; D018929:Cell Culture Techniques; D004285:Dogs; D006801:Humans; D042541:Intracellular Space / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000502:physiology*; D053139:Oseltamivir / Q000494:pharmacology*; D016865:Reassortant Viruses; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir