title: Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility.
abstract: Mutations of the conserved residues of influenza virus neuraminidase (NA) that are associated with NA inhibitor (NAI) resistance decrease the sialidase activity and/or stability of the NA, thus compromising viral fitness. In fact, clinically derived NAI-resistant variants with different NA mutations have shown different transmissibilities in ferrets (M. L. Herlocher, R. Truscon, S. Elias, H. Yen, N. A. Roberts, S. E. Ohmit, and A. S. Monto, J. Infect. Dis. 190:1627-1630, 2004). Molecular characterization of mutant viruses that have a homogeneous genetic background is required to determine the effect of single mutations at conserved NA residues. We generated recombinant viruses containing either the wild-type NA (RG WT virus) or a single amino acid change at NA residue 119 (RG E119V-NA virus) or 292 (RG R292K-NA virus) in the A/Wuhan/359/95 (H3N2) influenza virus background by reverse genetics. Both mutants showed decreased sensitivity to oseltamivir carboxylate, and the RG R292K-NA virus showed cross-resistance to zanamivir. We also observed differences between the two mutants in NA enzymatic activity and thermostability. The R292K mutation caused greater reduction of sialidase activity and thermostability than the E119V mutation. The NA defect caused by the R292K mutation was associated with compromised growth and transmissibility, whereas the growth and transmissibility of the RG E119V-NA virus were comparable to those of RG WT virus. Our results suggest that NAI-resistant influenza virus variants may differ substantially in fitness and transmissibility, depending on different levels of NA functional loss.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Yen
authors.forename: Louise M
authors.initials: LM
authors.lastname: Herlocher
authors.forename: Erich
authors.initials: E
authors.lastname: Hoffmann
authors.forename: Mikhail N
authors.initials: MN
authors.lastname: Matrosovich
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Monto
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004795:Enzyme Stability / Q000235:genetics; D005260:Female; D005289:Ferrets; D014644:Genetic Variation; D006146:Guanidines / Q000494:pharmacology; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development*; D009976:Orthomyxoviridae Infections / Q000635:transmission*; D053139:Oseltamivir; D011714:Pyrans / Q000494:pharmacology; D011995:Recombination, Genetic; D012794:Sialic Acids / Q000494:pharmacology; D013696:Temperature; D014779:Virus Replication / Q000235:genetics; D053243:Zanamivir
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir