title: Emergence of Hemagglutinin Mutations During the Course of Influenza Infection.
abstract: Influenza remains a significant cause of disease mortality. The ongoing threat of influenza infection is partly attributable to the emergence of new mutations in the influenza genome. Among the influenza viral gene products, the hemagglutinin (HA) glycoprotein plays a critical role in influenza pathogenesis, is the target for vaccines and accumulates new mutations that may alter the efficacy of immunization. To study the emergence of HA mutations during the course of infection, we employed a deep-targeted sequencing method. We used samples from 17 patients with active H1N1 or H3N2 influenza infections. These patients were not treated with antivirals. In addition, we had samples from five patients who were analyzed longitudinally. Thus, we determined the quantitative changes in the fractional representation of HA mutations during the course of infection. Across individuals in the study, a series of novel HA mutations directly altered the HA coding sequence were identified. Serial viral sampling revealed HA mutations that either were stable, expanded or were reduced in representation during the course of the infection. Overall, we demonstrated the emergence of unique mutations specific to an infected individual and temporal genetic variation during infection.
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, 94304, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Cushing
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Kamali
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Winters
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, 94304, United States.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Hopmans
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, 94304, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Bell
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, 94304, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Grimes
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States.
authors.forename: Li C
authors.initials: LC
authors.lastname: Xia
authors.affiliation: Depart of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Zhang
authors.affiliation: Ansun BioPharma, Inc., San Diego, CA, 92121, United States.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Moss
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States.|VA Palo Alto Health Care System, Palo Alto, CA 94304, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Holodniy
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, 94304, United States.|Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States.
authors.forename: Hanlee P
authors.initials: HP
authors.lastname: Ji
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D014611:Vaccination / Q000379:methods; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D014764:Viral Proteins