title: Accumulation of defective neuraminidase (NA) genes by influenza A viruses in the presence of NA inhibitors as a marker of reduced dependence on NA.
abstract: With the use of neuraminidase (NA) inhibitors (BCX-1812, oseltamivir, or zanamivir), drug-resistant variants of influenza A viruses were generated that lacked characteristic markers of resistance, such as substitutions in the NA active center or in the hemagglutinin. Drug resistance was associated with the accumulation of defective (Delta) RNA segments encoding NA. This phenomenon could be explained by reduced dependence of the virus on its NA activity. Analysis of the last isolates recovered from 11 volunteers, experimentally infected with influenza virus and treated with BCX-1812, revealed that they maintained full susceptibility to the drug in the NA inhibition assay (50% inhibitory concentration, 0.35-0.5 nM). The presence of DeltaRNA segments was detected in 1 of these isolates but was not found in the isolates recovered from placebo recipients (n = 8). Because of a lack of cell culture-based assays for susceptibility testing of human influenza viruses, detection of DeltaRNA segments should be considered an additional assay for monitoring of NA inhibitor resistance.
authors.affiliation: Department of Internal Medicine, Division of Epidemiology and Virology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Nedyalkova
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hayden
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Gubareva
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000146:Acids, Carbocyclic; D000818:Animals; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006146:Guanidines; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D053139:Oseltamivir; D010948:Viral Plaque Assay
chemical_list: D000081:Acetamides; D000146:Acids, Carbocyclic; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D053139:Oseltamivir; D009439:Neuraminidase; C414210:peramivir