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Abstract
Influenza A(H3N2) has been a major cause of seasonal influenza in humans since 1968, and has evolved by antigenic drift under the constantly changing human herd immunity. Increasing evidence suggests that the antigenic change occasionally occurred concomitant with the alterations of the N-glycosylation site profile and hemagglutination activity of the virion surface protein hemagglutinin (HA). However, the structural basis of these changes remains largely unclear. To address this issue, we performed molecular dynamics simulations of the glycosylated HA trimers of the A(H3N2), which has a novel pattern of Asn-X-Ser/Thr sequons unique in the new A(H3N2) epidemic clade 3C.2a and is characterized by attenuated ability to agglutinate nonhuman erythrocytes. Comparison of the equilibrated structures of the glycosylated HA trimers with and without the 3C.2a-specific mutations reveals that the mutations could induce a drastic reduction in the apical space for the ligand binding via glycan-shield rearrangement. The results suggest that the 3C.2a strain has evolved an HA structure that is advantageous for evading pre-existing antibodies, while also increasing the ligand binding specificity. These findings have structural implications for our understanding of the phenotypic changes, evolution, and fate of influenza A(H3N2).
Highlights
The hemagglutinin (HA) protein of influenza virus is a glycosylated type I integral membrane protein that protrudes from the mature virion surface and plays critical roles in viral interactions with hosts
Hemagglutination activity of the 3C.2a was significantly attenuated when measured with a conventional hemagglutination assay (Skowronski et al, 2016). These data suggest that certain structural changes occurred in the HA protein to confer selective advantages on the 3C.2a
Two structural models of the glycosylated HA trimers in a ligand-free state were constructed by homology modeling: a model for the A(H3N2) 2015/16 vaccine strain (A/Switzerland/9715293/2013) that belongs to the perishing clade 3C.3a (Figures 1, 2) and a model for A/Switzerland/9715293/2013 possessing the four 3C.2a-specific mutations on the HA globular heads (Ala128Thr, Asn144Ser, Ser159Tyr, and Lys160Thr)
Summary
The hemagglutinin (HA) protein of influenza virus is a glycosylated type I integral membrane protein that protrudes from the mature virion surface and plays critical roles in viral interactions with hosts. The oligosaccharides on the HA protein play key roles in viral antigenicity (Aytay and Schulze, 1991; Abe et al, 2004; Saito et al, 2004; Ping et al, 2008; Das et al, 2010; Wang et al, 2010; Wanzeck et al, 2011) and binding specificity/affinity to the cellular receptor (Gunther et al, 1993; Ohuchi et al, 1997; Gambaryan et al, 1998; Matrosovich et al, 1999; Tsuchiya et al, 2002; Wang et al, 2009; de Vries et al, 2010; Liao et al, 2010) It remains unclear how the 3C.2a mutations altered the HA structure and attenuated the hemagglutination activity with nonhuman erythrocytes. The obtained results predicted that the mutations could induce rearrangement of the glycan shield around the receptor-binding surface of the HA protein, leading to shrinkage of the ligandaccessible space
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