In Vitro Characterization of Multidrug-Resistant Influenza A(H1N1)pdm09 Viruses Carrying a Dual Neuraminidase Mutation Isolated from Immunocompromised Patients

  • Pathogens. 2020 Sep 2;9(9):725. doi: 10.3390/pathogens9090725.
Emi Takashita  1 ,  Seiichiro Fujisaki  1 ,  Masaru Yokoyama  2 ,  Masayuki Shirakura  1 ,  Hiroko Morita  1 ,  Kazuya Nakamura  1 ,  Noriko Kishida  1 ,  Tomoko Kuwahara  1 ,  Hironori Sato  2 ,  Ikuko Doi  3 ,  Yuji Sato  4 ,  Shinichi Takao  5 ,  Yukie Shimazu  5 ,  Takeshi Shimomura  6 ,  Takuo Ito  7 ,  Shinji Watanabe  1 ,  Takato Odagiri  1 ,  The Influenza Virus Surveillance Group Of Japan
Affiliations
  • 1. Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
  • 2. Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
  • 3. Ibaraki Prefectural Institute of Public Health, Ibaraki 310-0852, Japan.
  • 4. Tsukuba Memorial Hospital, Ibaraki 300-2622, Japan.
  • 5. Hiroshima Prefectural Technology Research Institute, Hiroshima 734-0007, Japan.
  • 6. National Hospital Organization Hiroshimanishi Medical Center, Hiroshima 739-0696, Japan.
  • 7. National Hospital Organization Kure Medical Center, Hiroshima 737-0023, Japan.
PMID: 32887429 DOI: 10.3390/pathogens9090725
Abstract

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.

Keywords
baloxavir; favipiravir; influenza; laninamivir; neuraminidase inhibitor; oseltamivir; peramivir; resistance; zanamivir.
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