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Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses

Author

Listed:
  • Susu Duan

    (St Jude Children’s Research Hospital)

  • Elena A. Govorkova

    (St Jude Children’s Research Hospital)

  • Justin Bahl

    (School of Public Health, The University of Texas Health Science Center at Houston
    Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School)

  • Hassan Zaraket

    (St Jude Children’s Research Hospital)

  • Tatiana Baranovich

    (St Jude Children’s Research Hospital)

  • Patrick Seiler

    (St Jude Children’s Research Hospital)

  • Kristi Prevost

    (St Jude Children’s Research Hospital)

  • Robert G. Webster

    (St Jude Children’s Research Hospital)

  • Richard J. Webby

    (St Jude Children’s Research Hospital)

Abstract

Oseltamivir-resistant H1N1 influenza viruses carrying the H275Y neuraminidase mutation predominated worldwide during the 2007–2009 seasons. Although several neuraminidase substitutions were found to be necessary to counteract the adverse effects of H275Y, the order and impact of evolutionary events involved remain elusive. Here we reconstruct H1N1 neuraminidase phylogeny during 1999–2009, estimate the timing and order of crucial amino acid changes and evaluate their impact on the biological outcome of the H275Y mutation. Of the 12 neuraminidase substitutions that occurred during 1999–2009, 5 (chronologically, V234M, R222Q, K329E, D344N, H275Y and D354G) are necessary for maintaining full neuraminidase function in the presence of the H275Y mutation by altering protein accumulation or enzyme affinity/activity. The sequential emergence and cumulative effects of these mutations clearly illustrate a role for epistasis in shaping the emergence and subsequent evolution of a drug-resistant virus population, which can be useful in understanding emergence of novel viral phenotypes of influenza.

Suggested Citation

  • Susu Duan & Elena A. Govorkova & Justin Bahl & Hassan Zaraket & Tatiana Baranovich & Patrick Seiler & Kristi Prevost & Robert G. Webster & Richard J. Webby, 2014. "Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6029
    DOI: 10.1038/ncomms6029
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    Cited by:

    1. Daniel Ellis & Julia Lederhofer & Oliver J. Acton & Yaroslav Tsybovsky & Sally Kephart & Christina Yap & Rebecca A. Gillespie & Adrian Creanga & Audrey Olshefsky & Tyler Stephens & Deleah Pettie & Mic, 2022. "Structure-based design of stabilized recombinant influenza neuraminidase tetramers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Ruipeng Lei & Timothy J. C. Tan & Andrea Hernandez Garcia & Yiquan Wang & Meghan Diefenbacher & Chuyun Teo & Gopika Gopan & Zahra Tavakoli Dargani & Qi Wen Teo & Claire S. Graham & Christopher B. Broo, 2022. "Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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