Abstract
Antigenic drift in the influenza A virus hemagglutinin (HA) is responsible for seasonal reformulation of influenza vaccines. Here, we address an important and largely overlooked issue in antigenic drift: how does the number and location of glycosylation sites affect HA evolution in man? We analyzed the glycosylation status of all full-length H1 subtype HA sequences available in the NCBI influenza database. We devised the “flow index” (FI), a simple algorithm that calculates the tendency for viruses to gain or lose consensus glycosylation sites. The FI predicts the predominance of glycosylation states among existing strains. Our analyses show that while the number of glycosylation sites in the HA globular domain does not influence the overall magnitude of variation in defined antigenic regions, variation focuses on those regions unshielded by glycosylation. This supports the conclusion that glycosylation generally shields HA from antibody-mediated neutralization, and implies that fitness costs in accommodating oligosaccharides limit virus escape via HA hyperglycosylation.
Highlights
The influenza A virus (IAV) hemagglutinin (HA) is a homotrimeric glycoprotein that initiates infection by attaching virus to host cell sialic acids and mediating fusion of viral and endosomal membranes [1]
Distribution of N-glycosylation sites in HA sequences We analyzed 1907 full-length H1 HA sequences from human, swine or avian viruses downloaded from the NCBI influenza virus resource
Glycosylation sites are located within 5 residues on either side of a Influenza A virus is highly susceptible to neutralizing antibodies specific for the viral hemagglutinin glycoprotein (HA), and is controlled by standard vaccines
Summary
The influenza A virus (IAV) hemagglutinin (HA) is a homotrimeric glycoprotein that initiates infection by attaching virus to host cell sialic acids and mediating fusion of viral and endosomal membranes [1]. HA consists of a fibrous stem inserted into the viral membrane supporting a globular domain containing three sialic acid binding sites (one per monomer). Most Abs neutralize infection by sterically blocking access of sialic acid receptors to the HA [5,6]. Based on locating single amino acid substitutions that enable escape from neutralization with monoclonal Abs (mAbs), physically distinct regions have been defined on the globular domains of H1 (Sa, Sb, Ca, Cb) and H3 (A, B, C, D, E) subtype HAs [7,8,9]. Differences in the location of the antigenic sites in the globular domain correlate with the differential location of consensus N-linked oligosaccharide attachment sites in the H1 (PR8) vs. H3 (HK) HAs used for antigenic analysis [9,10]
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