title: Influenza A virus hemagglutinin antibody escape promotes neuraminidase antigenic variation and drug resistance.
abstract: Drugs inhibiting the influenza A virus (IAV) neuraminidase (NA) are the cornerstone of anti-IAV chemotherapy and prophylaxis in man. Drug-resistant mutations in NA arise frequently in human isolates, limiting the therapeutic application of NA inhibitors. Here, we show that antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site leads to compensatory mutations in NA, resulting in NA antigenic variation and acquisition of drug resistance. These findings indicate that influenza A virus resistance to NA inhibitors can potentially arise from antibody driven HA escape, confounding analysis of influenza NA evolution in nature.
authors.affiliation: Laboratory of Viral Diseases, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Hensley
authors.forename: Suman R
authors.initials: SR
authors.lastname: Das
authors.forename: James S
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Adam L
authors.initials: AL
authors.lastname: Bailey
authors.forename: Loren M
authors.initials: LM
authors.lastname: Schmidt
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000940:Antigenic Variation / Q000235:genetics* / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics* / Q000276:immunology; D006388:Hemagglutinins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology; D008958:Models, Molecular; D009154:Mutation / Q000276:immunology / Q000502:physiology; D009439:Neuraminidase / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053139:Oseltamivir / Q000494:pharmacology / Q000627:therapeutic use; D053243:Zanamivir / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D006388:Hemagglutinins; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir