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Nat Commun. 2014 Oct 9;5:5029. doi: 10.1038/ncomms6029.

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

Author information

1
Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
2
1] School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, Texas 77030, USA [2] Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.

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.

PMID:
25297528
PMCID:
PMC4197134
DOI:
10.1038/ncomms6029
[Indexed for MEDLINE]
Free PMC Article

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