Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift
Scott E. Hensley,1
Suman R. Das,1
Adam L. Bailey,1
Loren M. Schmidt,1
Heather D. Hickman,1
Akila Jayaraman,2
Karthik Viswanathan,2
Rahul Raman,2
Ram Sasisekharan,2
Jack R. Bennink,1
Jonathan W. Yewdell1,*
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.
2 Harvard-MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
* To whom correspondence should be addressed. E-mail: jyewdell{at}mail.nih.gov
