Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift

• Published in: Science (American Association for the Advancement of Science) Vol. 326; no. 5953; pp. 734 - 736
• Main Authors: Hensley, Scott E, Das, Suman R, Bailey, Adam L, Schmidt, Loren M, Hickman, Heather D, Jayaraman, Akila, Viswanathan, Karthik, Raman, Rahul, Sasisekharan, Ram, Bennink, Jack R, Yewdell, Jonathan W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 30-10-2009; The American Association for the Advancement of Science
• Subjects: Amino acid substitution; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antigenic variation; Antigenic Variation - genetics; Antigenic Variation - immunology; Antigens; Binding sites; Biological and medical sciences; Cell Line; Cell surface receptors; Cellular biology; Cellular receptors; Fundamental and applied biological sciences. Psychology; Genetics; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Immune system; Influenza; Influenza A virus; Influenza A Virus, H1N1 Subtype - genetics; Influenza A Virus, H1N1 Subtype - immunology; Influenza Vaccines - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbiology; Models, Immunological; Mutation; Polyclonal antibodies; Receptors; Receptors, Virus - metabolism; Rodents; Serial Passage; Vaccines; Virology; Viruses; Virus; Genetic drift; Biological fixation; Influenzavirus A; Antigenic determinant; Hemagglutinin; Orthomyxoviridae; Affinity; Avidity; Monoclonal antibody; Immune evasion; Biological receptor
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1178258

Rapid antigenic evolution in the influenza A virus hemagglutinin precludes effective vaccination with existing vaccines. To understand this phenomenon, we passaged virus in mice immunized with influenza vaccine. Neutralizing antibodies selected mutants with single-amino acid hemagglutinin substitutions that increased virus binding to cell surface glycan receptors. Passaging these high-avidity binding mutants in naïve mice, but not immune mice, selected for additional hemagglutinin substitutions that decreased cellular receptor binding avidity. Analyzing a panel of monoclonal antibody hemagglutinin escape mutants revealed a positive correlation between receptor binding avidity and escape from polyclonal antibodies. We propose that in response to variation in neutralizing antibody pressure between individuals, influenza A virus evolves by adjusting receptor binding avidity via amino acid substitutions throughout the hemagglutinin globular domain, many of which simultaneously alter antigenicity.