title: Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates.
abstract: The number of patients infected with H7N9 influenza virus has been increasing since 2013. We examined the efficacy of neuraminidase (NA) inhibitors and the efficacy of a vaccine against an H7N9 influenza virus, A/Anhui/1/2013 (H7N9), isolated from a patient in a cynomolgus macaque model. NA inhibitors (oseltamivir and peramivir) barely reduced the total virus amount because of the emergence of resistant variants with R289K or I219T in NA [residues 289 and 219 in N9 of A/Anhui/1/2013 (H7N9) correspond to 292 and 222 in N2, respectively] in three of the six treated macaques, whereas subcutaneous immunization of an inactivated vaccine derived from A/duck/Mongolia/119/2008 (H7N9) prevented propagation of A/Anhui/1/2013 (H7N9) in all vaccinated macaques. The percentage of macaques in which variant H7N9 viruses with low sensitivity to the NA inhibitors were detected was much higher than that of macaques in which variant H5N1 highly pathogenic influenza virus was detected after treatment with one of the NA inhibitors in our previous study. The virus with R289K in NA was reported in samples from human patients, whereas that with I219T in NA was identified for the first time in this study using macaques, though no variant H7N9 virus was reported in previous studies using mice. Therefore, the macaque model enables prediction of the frequency of emerging H7N9 virus resistant to NA inhibitors in vivo. Since H7N9 strains resistant to NA inhibitors might easily emerge compared to other influenza viruses, monitoring of the emergence of variants is required during treatment of H7N9 influenza virus infection with NA inhibitors.
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan yasushii@belle.shiga-med.ac.jp maruichi@belle.shiga-med.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Shichinohe
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ishigaki
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kitagawa
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Sasamura
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shiohara
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Doi
authors.affiliation: Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Okamatsu
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Division of Pathology and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan yasushii@belle.shiga-med.ac.jp maruichi@belle.shiga-med.ac.jp.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000276:immunology; D064766:Influenza A Virus, H7N9 Subtype / Q000187:drug effects* / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D008251:Macaca; D051379:Mice; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology; D011323:Primates; D014611:Vaccination / Q000379:methods; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D007252:Influenza Vaccines; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase; C414210:peramivir