title: Presence of oseltamivir-resistant pandemic A/H1N1 minor variants before drug therapy with subsequent selection and transmission.
abstract: A small proportion (1%-1.5%) of 2009 pandemic influenza A/H1N1 virus strains (A[H1N1]pdm09) are oseltamivir resistant, almost exclusively because of a H275Y mutation in the neuraminidase protein. However, many individuals infected with resistant strains had not received antivirals. Whether drug-resistant viruses are initially present as minor variants in untreated individuals before they emerge as the dominant strain in a virus population is of great importance for predicting the speed at which resistance will arise. To address this issue, we used ultra-deep sequencing of viral populations from serial nasopharyngeal specimens from an immunocompromised child and from 2 individuals in a household outbreak. We observed that the Y275 mutation was present as a minor variant in infected hosts before the onset of therapy. We also found evidence for the transmission of this drug-resistant variant with drug-susceptible viruses. These observations provide important information on the relative fitness of the Y275 mutation in the absence of oseltamivir treatment.
authors.affiliation: Department of Computational & Systems Biology, Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. elg21@pitt.edu
authors.forename: Elodie
authors.initials: E
authors.lastname: Ghedin
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.forename: Jay V
authors.initials: JV
authors.lastname: DePasse
authors.forename: Lady Tatiana
authors.initials: LT
authors.lastname: Pinilla
authors.forename: Adam
authors.initials: A
authors.lastname: Fitch
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Hamelin
authors.forename: Jesse
authors.initials: J
authors.lastname: Papenburg
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000235:genetics; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics*; D007251:Influenza, Human / Q000188:drug therapy* / Q000635:transmission / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053243:Zanamivir / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir