title: Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir.
abstract: Volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) virus and treated with the neuraminidase (NA) inhibitor oseltamivir were monitored for the emergence of drug-resistant variants. Two (4%) of 54 resistant viruses were detected by NA inhibition assay among last-day isolates recovered from 54 drug recipients. They bore a substitution His274Tyr in the NA. Hemagglutinin (HA) variants detected in the placebo group differed from the egg-adapted inoculum virus by virtue of amino acid substitutions at residues 137, 225, or both. These variants had a higher affinity for Neu5Ac(alpha2-6)Gal-containing receptors, which are characteristic of human respiratory epithelium, than for Neu5Ac(alpha2-3)Gal-containing receptors, which are typical of chicken egg allantoic membrane. Although appearing to be more sensitive to oseltamivir in humans, the variants with increased affinity for Neu5Ac(alpha2-6)Gal receptors were less sensitive than the Neu5Ac(alpha2-3)Gal-binding variants in Madin-Darby canine kidney cells. Thus, HA affinity for receptors is an essential feature of influenza virus susceptibility to NA inhibitors, both in cell culture and in humans.
authors.affiliation: Department of Internal Medicine, Division of Epidemiology and Virology, University of Virginia, PO Box 473, Charlottesville, VA 22908, USA. lvg9b@virginia.edu
authors.forename: L V
authors.initials: LV
authors.lastname: Gubareva
authors.forename: L
authors.initials: L
authors.lastname: Kaiser
authors.forename: M N
authors.initials: MN
authors.lastname: Matrosovich
authors.forename: Y
authors.initials: Y
authors.lastname: Soo-Hoo
authors.forename: F G
authors.initials: FG
authors.lastname: Hayden
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D002460:Cell Line; D004285:Dogs; D004352:Drug Resistance, Microbial; D014644:Genetic Variation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008826:Microbial Sensitivity Tests / Q000379:methods; D008969:Molecular Sequence Data; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D053139:Oseltamivir; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism; D010948:Viral Plaque Assay
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; D053139:Oseltamivir; D009439:Neuraminidase