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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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Mean values of variability of H1 globular domain.Mean values of variability at A) non-glycosylated regions of HA globular domain; B) glycosylation sites that are glycosylation competent (i.e. possess consensus glycosylation sites); C) regions that are glycosylated in HA but lack glycosylation sequences; D) non-glycosylated regions of HA from sequences with 3 glycosylation sequences. To reconstruct this plot, glycosylated regions considered positions 91,129 and 162 +/−3 amino acids. Confidence intervals estimated by bootstrap of 500 replicates [44]. Schematic representations of the regions used to calculate mean values of A, B, C and D are shown on right.
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ppat-1001211-g004: Mean values of variability of H1 globular domain.Mean values of variability at A) non-glycosylated regions of HA globular domain; B) glycosylation sites that are glycosylation competent (i.e. possess consensus glycosylation sites); C) regions that are glycosylated in HA but lack glycosylation sequences; D) non-glycosylated regions of HA from sequences with 3 glycosylation sequences. To reconstruct this plot, glycosylated regions considered positions 91,129 and 162 +/−3 amino acids. Confidence intervals estimated by bootstrap of 500 replicates [44]. Schematic representations of the regions used to calculate mean values of A, B, C and D are shown on right.

Mentions: Each combination of glycosylation sites generates a similar pattern: glycosylation minimizes variation around its own site while focusing variation onto non-glycosylated sites. The statistical significance of this conclusion is shown in Figure 4. A simple interpretation for this finding is that oligosaccharides shield antigenic regions from Ab neutralization, shifting variation to unshielded sites. This is consistent with the observation that viruses cluster in the PCA plot based on a common number of glycosylation sites in the globular domain and not year of collection (Figure S2), which demonstrates that they are highly homologous in the hypervariable regions of the globular domain.


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)

Mean values of variability of H1 globular domain.Mean values of variability at A) non-glycosylated regions of HA globular domain; B) glycosylation sites that are glycosylation competent (i.e. possess consensus glycosylation sites); C) regions that are glycosylated in HA but lack glycosylation sequences; D) non-glycosylated regions of HA from sequences with 3 glycosylation sequences. To reconstruct this plot, glycosylated regions considered positions 91,129 and 162 +/−3 amino acids. Confidence intervals estimated by bootstrap of 500 replicates [44]. Schematic representations of the regions used to calculate mean values of A, B, C and D are shown on right.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991263&req=5

ppat-1001211-g004: Mean values of variability of H1 globular domain.Mean values of variability at A) non-glycosylated regions of HA globular domain; B) glycosylation sites that are glycosylation competent (i.e. possess consensus glycosylation sites); C) regions that are glycosylated in HA but lack glycosylation sequences; D) non-glycosylated regions of HA from sequences with 3 glycosylation sequences. To reconstruct this plot, glycosylated regions considered positions 91,129 and 162 +/−3 amino acids. Confidence intervals estimated by bootstrap of 500 replicates [44]. Schematic representations of the regions used to calculate mean values of A, B, C and D are shown on right.
Mentions: Each combination of glycosylation sites generates a similar pattern: glycosylation minimizes variation around its own site while focusing variation onto non-glycosylated sites. The statistical significance of this conclusion is shown in Figure 4. A simple interpretation for this finding is that oligosaccharides shield antigenic regions from Ab neutralization, shifting variation to unshielded sites. This is consistent with the observation that viruses cluster in the PCA plot based on a common number of glycosylation sites in the globular domain and not year of collection (Figure S2), which demonstrates that they are highly homologous in the hypervariable regions of the globular domain.

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