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Glycosylation focuses sequence variation in the influenza A virus H1 hemagglutinin globular domain.

Das SR, Puigbò P, Hensley SE, Hurt DE, Bennink JR, Yewdell JW - PLoS Pathog. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: NIAID, Bethesda, MA, USA.

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.

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Relationship between amino acid variability and presence of glycosylation sites in H1 globular domain.The plots correspond to H1 HA with the glycosylation sites indicated on the X-axis. Sequences with 2 glycosylation sites in regions 129 and 162 were not found. Green bars plot the number of amino acids present at each position in the group of isolates with specific number of oligosaccharide sites indicated, black lines are the running average of two neighboring positions. The positions and the number of different amino acid residues in each hypervariable region (in parentheses) are shown in red, i.e., those regions that have a variability of 3 standard deviations over the mean value (red line). Number of isolates available for each glycosylation stat: zero sites, 21 isolates; 1 site, position 91, 420 isolates; position 129, 10 isolates; position 162, 4 isolates; 2 sites, positions 91, 129, 34 isolates; 91, 162, 33 isolates; 3 sites, 1118 isolates.
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ppat-1001211-g003: Relationship between amino acid variability and presence of glycosylation sites in H1 globular domain.The plots correspond to H1 HA with the glycosylation sites indicated on the X-axis. Sequences with 2 glycosylation sites in regions 129 and 162 were not found. Green bars plot the number of amino acids present at each position in the group of isolates with specific number of oligosaccharide sites indicated, black lines are the running average of two neighboring positions. The positions and the number of different amino acid residues in each hypervariable region (in parentheses) are shown in red, i.e., those regions that have a variability of 3 standard deviations over the mean value (red line). Number of isolates available for each glycosylation stat: zero sites, 21 isolates; 1 site, position 91, 420 isolates; position 129, 10 isolates; position 162, 4 isolates; 2 sites, positions 91, 129, 34 isolates; 91, 162, 33 isolates; 3 sites, 1118 isolates.

Mentions: Does glycosylation focus drift on selected antigenic sites? We correlated the location of glycosylation sites with the variability at individual residues in the globular domain (Figure 3). This revealed that glycosylation alters the focus of sequence variation. In HAs lacking glycosylation sites in the antigenic domain, variability peaks near residue 135. Acquisition of a glycosylation site in the same region (129) results in reduction of variability in that region, and increase in variability at residues 78, 159, and 228, which represent the Cb, Sb, and Ca antigenic sites. Acquisition of two glycosylation sites at 91 and 129 now focuses variation at residues 165 and 190. With all three glycosylation sites utilized, variation is now focused around residues 190 and 191. Interestingly, positions 190 and 228 greatly influence HA receptor specificity for α-2,3 vs. α-2,6 of the sialic residue [31], [32].


Glycosylation focuses sequence variation in the influenza A virus H1 hemagglutinin globular domain.

Das SR, Puigbò P, Hensley SE, Hurt DE, Bennink JR, Yewdell JW - PLoS Pathog. (2010)

Relationship between amino acid variability and presence of glycosylation sites in H1 globular domain.The plots correspond to H1 HA with the glycosylation sites indicated on the X-axis. Sequences with 2 glycosylation sites in regions 129 and 162 were not found. Green bars plot the number of amino acids present at each position in the group of isolates with specific number of oligosaccharide sites indicated, black lines are the running average of two neighboring positions. The positions and the number of different amino acid residues in each hypervariable region (in parentheses) are shown in red, i.e., those regions that have a variability of 3 standard deviations over the mean value (red line). Number of isolates available for each glycosylation stat: zero sites, 21 isolates; 1 site, position 91, 420 isolates; position 129, 10 isolates; position 162, 4 isolates; 2 sites, positions 91, 129, 34 isolates; 91, 162, 33 isolates; 3 sites, 1118 isolates.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991263&req=5

ppat-1001211-g003: Relationship between amino acid variability and presence of glycosylation sites in H1 globular domain.The plots correspond to H1 HA with the glycosylation sites indicated on the X-axis. Sequences with 2 glycosylation sites in regions 129 and 162 were not found. Green bars plot the number of amino acids present at each position in the group of isolates with specific number of oligosaccharide sites indicated, black lines are the running average of two neighboring positions. The positions and the number of different amino acid residues in each hypervariable region (in parentheses) are shown in red, i.e., those regions that have a variability of 3 standard deviations over the mean value (red line). Number of isolates available for each glycosylation stat: zero sites, 21 isolates; 1 site, position 91, 420 isolates; position 129, 10 isolates; position 162, 4 isolates; 2 sites, positions 91, 129, 34 isolates; 91, 162, 33 isolates; 3 sites, 1118 isolates.
Mentions: Does glycosylation focus drift on selected antigenic sites? We correlated the location of glycosylation sites with the variability at individual residues in the globular domain (Figure 3). This revealed that glycosylation alters the focus of sequence variation. In HAs lacking glycosylation sites in the antigenic domain, variability peaks near residue 135. Acquisition of a glycosylation site in the same region (129) results in reduction of variability in that region, and increase in variability at residues 78, 159, and 228, which represent the Cb, Sb, and Ca antigenic sites. Acquisition of two glycosylation sites at 91 and 129 now focuses variation at residues 165 and 190. With all three glycosylation sites utilized, variation is now focused around residues 190 and 191. Interestingly, positions 190 and 228 greatly influence HA receptor specificity for α-2,3 vs. α-2,6 of the sialic residue [31], [32].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: NIAID, Bethesda, MA, USA.

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.

Show MeSH
Related in: MedlinePlus