title: Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance.
abstract: Mixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug resistance in these circumstances, we used a deep sequencing approach to survey the viral population from an immunosuppressed patient infected with H1N1/2009 influenza and treated with neuraminidase inhibitors. This patient harbored 3 genetic variants from 2 phylogenetically distinct viral clades of pandemic H1N1/2009, strongly suggestive of mixed infection. Strikingly, one of these variants also developed drug resistance de novo in response to oseltamivir treatment. Immunocompromised individuals may, therefore, constitute an important source of genetic and phenotypic diversity, both through mixed infection and de novo mutation.
authors.affiliation: Center for Vaccine Research, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. elg21@pitt.edu
authors.forename: Elodie
authors.initials: E
authors.lastname: Ghedin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Laplante
authors.forename: Jay
authors.initials: J
authors.lastname: DePasse
authors.forename: David E
authors.initials: DE
authors.lastname: Wentworth
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Santos
authors.forename: Martha L
authors.initials: ML
authors.lastname: Lepow
authors.forename: Joanne
authors.initials: J
authors.lastname: Porter
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stellrecht
authors.forename: Xudong
authors.initials: X
authors.lastname: Lin
authors.forename: Darwin
authors.initials: D
authors.lastname: Operario
authors.forename: Sara
authors.initials: S
authors.lastname: Griesemer
authors.forename: Adam
authors.initials: A
authors.lastname: Fitch
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Halpin
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Stockwell
authors.forename: David J
authors.initials: DJ
authors.lastname: Spiro
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.forename: Kirsten
authors.initials: K
authors.lastname: St George
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000494:pharmacology*; D044822:Biodiversity; D024882:Drug Resistance, Viral; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016867:Immunocompromised Host; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D007251:Influenza, Human / Q000453:epidemiology / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D053139:Oseltamivir / Q000494:pharmacology*; D058873:Pandemics; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D017385:Sequence Homology
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D053139:Oseltamivir