Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift

Abstract

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. 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.Influenza A virus remains an important human pathogen due largely to its ability to evade antibodies specific for its attachment protein, the hemagglutinin (HA). This "antigenic drift" is due to accumulation of amino acid substitutions in HA epitopes recognized by antibodies that neutralize viral infectivity by blocking interaction of HA with sialic acid residues on hostcell membranes (1-3). The H1 subtype HA has four antigenic sites recognized by monoclonal antibodies with high neutralizing activity, designated Sa, Sb, Ca, and Cb (4). How can HA escape polyclonal antibodies given that the frequency of variants with simultaneous multiple point mutations is exceedingly low (5)? A popular model posits sequential selection by different individuals whose antibody responses focus on different individual antigenic sites (6,7).To better understand how antigenic drift occurs in human populations, we revisited classical experiments modeling drift in outbred Swiss mice (8). We generated three separate infectious stocks of the mouse-adapted strain A/Puerto Rico/8/34 (H1N1) (PR8) in MDCK cells using

Genome plasticity of triple-reassortant H1N1 influenza A virus during infection of vaccinated pigs

“…However, our results also showed that nucleotide substitutions can occur in the signal peptide and the HA2 region of the HA, which were not evaluated by Murcia et al (2012). In addition, other factors in our study, such as the group housing conditions, which facilitated greater interaction between pigs compared with previous studies where pairs of individuals were used to measure intra-host diversity of IAV (Hensley et al, 2009;Murcia et al, 2010Murcia et al, , 2012, may have had an effect on the increased overall genetic diversity.…”

The evolutionary dynamics of influenza A virus adaptation to mammalian hosts

“…However, we urge caution in these interpretations, as our understanding of the selective forces on HA and NA is still limited. While much attention has focused on the selection of mutations in known HA antibody epitopes, other regions of HA and NA may contribute to viral fitness through glycosylation [36], compensatory or epistatic interactions [37] or increased avidity for host cell receptors [38]. Further, adaptive evolution, even when not directly driven by humoural immunity, may be more commonly tolerated on macromolecular surfaces owing to stronger structural constraints on internal residues [39].…”

Early Cytokine Dysregulation and Viral Replication Are Associated with Mortality During Lethal Influenza Infection

“…In addition to circulating seasonal strains, natural IAV infections in zoonotic reservoirs undergo antigenic drift (12,13) and antigenic shift (19) that efficiently evade host immune responses and cause extensive morbidity when transmitted to humans. Complications associated with swine (H1N1) and avian (H5N1, H7N9) IAV infection includes inflammation of the airways, epithelial necrosis, edema, hemorrhaging, and respiratory failure (8,29,44).…”