N-linked glycosylation in the hemagglutinin of influenza A viruses

Abstract

Since the 1918 influenza A virus (IAV) pandemic, H1N1 viruses have circulated in human populations. The hemagglutinin (HA) of IAV determines viral antigenicity and often undergoes N-linked glycosylation (NLG) at several sites. Interestingly, structural analysis of the 1918 and 2009 H1N1 pandemic viruses revealed antigenic similarities attributable to the conserved epitopes and the NLG statuses of their HA proteins. NLG of the globular head of HA is known to modulate the antigenicity, fusion activity, virulence, receptor-binding specificity, and immune evasion of IAV. In addition, the HA of IAV often retains additional mutations. These supplemental mutations compensate for the attenuation of viral properties resulting from the introduced NLG. In human H1N1 viruses, the number and location of NLG sites has been regulated in accordance with the antigenic variability of the NLG-targeted antibody-binding site. The relationship between the NLG and the antigenic variance in HA appears to be stably controlled in the viral context.

Fig. 1

NLG of the globular head of H1 HA during each time period. Using the HA crystal structure of the A/California/04/2009 virus (PDB ID: 3LZG), the possible N-linked glycans on the head of H1 HA from Table 1 were evaluated. Potential glycosites (red) near the RBS (yellow) are indicated by the H3 numbering. NLG, N-linked glycosylation; HA, hemagglutinin; RBS, receptor-binding site.

Fig. 2

The prediction of potential glycosites on the head of H1 HA. The 3-D crystal structure of the HA trimer of the A/California/04/2009 virus (PDB ID: 3LZG) was modified by the PyMol program to locate potential glycosites (yellow) at the membrane-distal region with top (A) and tilt (B) views. Among the five glycosites, four of them were identified in the SA antigenic site, and glycosite 131 (H3 numbering) was located at the vicinity of the receptor-binding site (RBS in magenta). HA, hemagglutinin; SA, sialic acid.

Fig. 3

The antigenic variability and the number of N-linked glycans on the head (Sa antigenic site) of H1 HA. The variance in the amino acids (indicated at the left) in the Sa antigenic site of H1 HA was modified from the work of Sun, et al. published in 2012. For comparison, the numbers of N-linked glycans (indicated at the right) in the membrane-distal region of H1 HA were collected from the works of Wei, et al. and Sun, et al. and were supplemented with the HA sequences of the hH1N1 viruses available from the National Center for Biotechnology Information of the United States. NLG, N-linked glycosylation; HA, hemagglutinin.