In Vitro Characterization of Multidrug-Resistant Influenza A(H1N1)pdm09 Viruses Carrying a Dual Neuraminidase Mutation Isolated from Immunocompromised Patients
Emi Takashita,
Seiichiro Fujisaki,
Masaru Yokoyama,
Masayuki Shirakura,
Hiroko Morita,
Kazuya Nakamura,
Noriko Kishida,
Tomoko Kuwahara,
Hironori Sato,
Ikuko Doi,
Yuji Sato,
Shinichi Takao,
Yukie Shimazu,
Takeshi Shimomura,
Takuo Ito,
Shinji Watanabe,
Takato Odagiri,
on behalf of The Influenza Virus Surveillance Group of Japan
Affiliations
Emi Takashita
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Seiichiro Fujisaki
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Masaru Yokoyama
Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Masayuki Shirakura
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Hiroko Morita
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Kazuya Nakamura
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Noriko Kishida
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Tomoko Kuwahara
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Hironori Sato
Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Ikuko Doi
Ibaraki Prefectural Institute of Public Health, Ibaraki 310-0852, Japan
Yuji Sato
Tsukuba Memorial Hospital, Ibaraki 300-2622, Japan
Shinichi Takao
Hiroshima Prefectural Technology Research Institute, Hiroshima 734-0007, Japan
Yukie Shimazu
Hiroshima Prefectural Technology Research Institute, Hiroshima 734-0007, Japan
Takeshi Shimomura
National Hospital Organization Hiroshimanishi Medical Center, Hiroshima 739-0696, Japan
Takuo Ito
National Hospital Organization Kure Medical Center, Hiroshima 737-0023, Japan
Shinji Watanabe
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Takato Odagiri
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
on behalf of The Influenza Virus Surveillance Group of Japan
Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.
