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J Virol. 2014 Oct 15. pii: JVI.02485-14. [Epub ahead of print]
Profiling and characterization of potentially multidrug-resistant influenza neuraminidase 1 (N1) strains against neuraminidase inhibitors.
Baek YH1, Song MS2, Lee EY3, Kim YI1, Kim EH1, Park SJ1, Park KJ1, Kwon HI1, Pascua PN1, Lim GJ1, Kim S1, Yoon SW4, Kim MH5, Webby RJ6, Choi YK7.
Author information
Abstract
Neuraminidase inhibitors (NAIs) have been widely used to control influenza infection, but their increased use could promote global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened known mutation(s) that could confer multidrug resistance to currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA genes (catalytic residues, R152K and R292K; framework residues, E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single- and double-mutant viruses recovered in the backbone of pH1N1, 4 variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition to all the NAIs and 2 variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the 9 recombinant H5N1 viruses, 4 variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition to all the NAIs, though their overall viral fitness was impaired in vitro and/or in vivo. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance to pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection.
IMPORTANCE:
There has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutants in vitro and in vivo. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition to all the NAIs tested in both the backbone of the 2009 H1N1 pandemic (pH1N1) and highly pathogenic avian influenza H5N1 viruses. Furthermore, E119D and E119D-H274Y mutants in the pH1N1 background maintained overall fitness properties in vitro and in vivo. Our study highlights the importance of vigilance and continued surveillance of potential NAI multidrug-resistant influenza variants as well as the development of alternative therapeutics.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25320319
[PubMed - as supplied by publisher]
Profiling and characterization of potentially multidrug-resistant influenza neuraminidase 1 (N1) strains against neuraminidase inhibitors.
Baek YH1, Song MS2, Lee EY3, Kim YI1, Kim EH1, Park SJ1, Park KJ1, Kwon HI1, Pascua PN1, Lim GJ1, Kim S1, Yoon SW4, Kim MH5, Webby RJ6, Choi YK7.
Author information
Abstract
Neuraminidase inhibitors (NAIs) have been widely used to control influenza infection, but their increased use could promote global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened known mutation(s) that could confer multidrug resistance to currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA genes (catalytic residues, R152K and R292K; framework residues, E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single- and double-mutant viruses recovered in the backbone of pH1N1, 4 variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition to all the NAIs and 2 variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the 9 recombinant H5N1 viruses, 4 variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition to all the NAIs, though their overall viral fitness was impaired in vitro and/or in vivo. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance to pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection.
IMPORTANCE:
There has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutants in vitro and in vivo. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition to all the NAIs tested in both the backbone of the 2009 H1N1 pandemic (pH1N1) and highly pathogenic avian influenza H5N1 viruses. Furthermore, E119D and E119D-H274Y mutants in the pH1N1 background maintained overall fitness properties in vitro and in vivo. Our study highlights the importance of vigilance and continued surveillance of potential NAI multidrug-resistant influenza variants as well as the development of alternative therapeutics.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25320319
[PubMed - as supplied by publisher]
