title: Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses.
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.
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Susu
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
authors.affiliation: 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.
authors.forename: Justin
authors.initials: J
authors.lastname: Bahl
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Zaraket
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Baranovich
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Seiler
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Prevost
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, Tennessee 38105, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
mesh_terms: D000818:Animals; D001483:Base Sequence; D001499:Bayes Theorem; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics*; D019143:Evolution, Molecular; D005289:Ferrets; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D061985:Madin Darby Canine Kidney Cells; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics*; D009439:Neuraminidase / Q000235:genetics*; D053139:Oseltamivir; D010802:Phylogeny; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D053139:Oseltamivir; D009439:Neuraminidase