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Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors.
J Virol. 2015 Jan; 89(1):287-99.JV

Abstract

Neuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the 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 a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding 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, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of 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 on 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 by all of 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 virus variants, as well as the development of alternative therapeutics.

Authors+Show Affiliations

College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea.Viral Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Youseong-gu, Daejeon, Republic of Korea.Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea Biosystems and Bioengineering Program, University of Science and Technology, Daejeon, Republic of Korea.Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.College of Medicine and Medical Research Institute, Chungbuk National University, Seowon-gu, Cheongju, Republic of Korea choiki55@chungbuk.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25320319

Citation

Baek, Yun Hee, et al. "Profiling and Characterization of Influenza Virus N1 Strains Potentially Resistant to Multiple Neuraminidase Inhibitors." Journal of Virology, vol. 89, no. 1, 2015, pp. 287-99.
Baek YH, Song MS, Lee EY, et al. Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. J Virol. 2015;89(1):287-99.
Baek, Y. H., Song, M. S., Lee, E. Y., Kim, Y. I., Kim, E. H., Park, S. J., Park, K. J., Kwon, H. I., Pascua, P. N., Lim, G. J., Kim, S., Yoon, S. W., Kim, M. H., Webby, R. J., & Choi, Y. K. (2015). Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. Journal of Virology, 89(1), 287-99. https://doi.org/10.1128/JVI.02485-14
Baek YH, et al. Profiling and Characterization of Influenza Virus N1 Strains Potentially Resistant to Multiple Neuraminidase Inhibitors. J Virol. 2015;89(1):287-99. PubMed PMID: 25320319.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. AU - Baek,Yun Hee, AU - Song,Min-Suk, AU - Lee,Eun-Young, AU - Kim,Young-il, AU - Kim,Eun-Ha, AU - Park,Su-Jin, AU - Park,Kuk Jin, AU - Kwon,Hyeok-il, AU - Pascua,Philippe Noriel Q, AU - Lim,Gyo-Jin, AU - Kim,Semi, AU - Yoon,Sun-Woo, AU - Kim,Myung Hee, AU - Webby,Richard J, AU - Choi,Young-Ki, Y1 - 2014/10/15/ PY - 2014/10/17/entrez PY - 2014/10/17/pubmed PY - 2015/3/17/medline SP - 287 EP - 99 JF - Journal of virology JO - J Virol VL - 89 IS - 1 N2 - UNLABELLED: Neuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the 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 a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding 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, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of 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 on 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 by all of 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 virus variants, as well as the development of alternative therapeutics. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/25320319/Profiling_and_characterization_of_influenza_virus_N1_strains_potentially_resistant_to_multiple_neuraminidase_inhibitors_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=25320319 DB - PRIME DP - Unbound Medicine ER -