title: Restoration of virulence of escape mutants of H5 and H9 influenza viruses by their readaptation to mice.
abstract: Antigenic mapping of the haemagglutinin (HA) molecule of H5 and H9 influenza viruses by selecting escape mutants with monoclonal anti-HA antibodies and subjecting the selected viruses to immunological analysis and sequencing has previously been performed. The viruses used as wild-type strains were mouse-adapted variants of the original H5 and H9 isolates. Phenotypic characterization of the escape mutants revealed that the amino acid change in HA that conferred resistance to a monoclonal antibody was sometimes associated with additional effects, including decreased virulence for mice. In the present study, the low-virulence H5 and H9 escape mutants were readapted to mice. Analysis of the readapted variants revealed that the reacquisition of virulence was not necessarily achieved by reacquisition of the wild-type HA gene sequence, but was also associated either with the removal of a glycosylation site (the one acquired previously by the escape mutant) without the exact restoration of the initial wild-type amino acid sequence, or, for an H5 escape mutant that had no newly acquired glycosylation sites, with an additional amino acid change in a remote part of the HA molecule. The data suggest that such 'compensating' mutations, removing the damaging effects of antibody-selected amino acid changes, may be important in the course of influenza virus evolution.
authors.affiliation: The D. I. Ivanovsky Institute of Virology, 16 Gamaleya Street, 123098 Moscow, Russia.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Rudneva
authors.affiliation: Division of Virology, Department of Infectious Diseases, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.|The D. I. Ivanovsky Institute of Virology, 16 Gamaleya Street, 123098 Moscow, Russia.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Ilyushina
authors.affiliation: The D. I. Ivanovsky Institute of Virology, 16 Gamaleya Street, 123098 Moscow, Russia.
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Timofeeva
authors.affiliation: Division of Virology, Department of Infectious Diseases, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.affiliation: The D. I. Ivanovsky Institute of Virology, 16 Gamaleya Street, 123098 Moscow, Russia.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Kaverin
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000940:Antigenic Variation / Q000235:genetics*; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D009980:Influenza A virus / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D051379:Mice; D014774:Virulence
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus