Predicting the Antigenic Structure of the Pandemic (H1N1) 2009 Influenza Virus Hemagglutinin

Abstract

The pandemic influenza virus (2009 H1N1) was recently introduced into the human population. The hemagglutinin (HA) gene of 2009 H1N1 is derived from “classical swine H1N1” virus, which likely shares a common ancestor with the human H1N1 virus that caused the pandemic in 1918, whose descendant viruses are still circulating in the human population with highly altered antigenicity of HA. However, information on the structural basis to compare the HA antigenicity among 2009 H1N1, the 1918 pandemic, and seasonal human H1N1 viruses has been lacking. By homology modeling of the HA structure, here we show that HAs of 2009 H1N1 and the 1918 pandemic virus share a significant number of amino acid residues in known antigenic sites, suggesting the existence of common epitopes for neutralizing antibodies cross-reactive to both HAs. It was noted that the early human H1N1 viruses isolated in the 1930s–1940s still harbored some of the original epitopes that are also found in 2009 H1N1. Interestingly, while 2009 H1N1 HA lacks the multiple N-glycosylations that have been found to be associated with an antigenic change of the human H1N1 virus during the early epidemic of this virus, 2009 H1N1 HA still retains unique three-codon motifs, some of which became N-glycosylation sites via a single nucleotide mutation in the human H1N1 virus. We thus hypothesize that the 2009 H1N1 HA antigenic sites involving the conserved amino acids will soon be targeted by antibody-mediated selection pressure in humans. Indeed, amino acid substitutions predicted here are occurring in the recent 2009 H1N1 variants. The present study suggests that antibodies elicited by natural infection with the 1918 pandemic or its early descendant viruses play a role in specific immunity against 2009 H1N1, and provides an insight into future likely antigenic changes in the evolutionary process of 2009 H1N1 in the human population.

Genomic signatures and antiviral drug susceptibility profile of A(H1N1)pdm09

“…Previous studies have also reported dominant circulation of this strain worldwide and suggested this is a consequence of enhanced viral fitness. 9,10 Within HA1, there was no evidence of evolutionary trends, in agreement with the genetic and antigenic homogeneity of A(H1N1)pdm09. 11 The location of amino acid substitutions observed in HA1 however, suggests these could result in phenotypic changes; the D222E substitution is located within a loop of the receptor-binding site, A73T and S185N within the putative antigenic sites Cb and Sb, respectively, and K119N has been reported to result in creation of a potential N-glycosylation site.…”

“…11 The location of amino acid substitutions observed in HA1 however, suggests these could result in phenotypic changes; the D222E substitution is located within a loop of the receptor-binding site, A73T and S185N within the putative antigenic sites Cb and Sb, respectively, and K119N has been reported to result in creation of a potential N-glycosylation site. 9,12 Correlation of these mutations with particular phenotypes, binding specificity or clinical outcome of infection however, needs further investigation.…”

Pandemic H1N1 Influenza A Viruses Are Resistant to the Antiviral Activities of Innate Immune Proteins of the Collectin and Pentraxin Superfamilies

“…In the process of antigenic drift, accumulation of glycosylation on the head of HA may mask or modify neutralizing epitopes on the HA surface (24,58). Recent seasonal H1N1 viruses carry three to five sites of N-linked glycosylation on the globular head of HA, whereas SC1918 and Cal/09 A(H1N1) pdm viruses have a single site at Asn 104 (25)(26)(27)59). The HA molecules expressed by H1N1 viruses from the 1930s (NWS/33, WS/33, and PR8/34) used in our studies were poorly glycosylated and, accordingly, all strains were resistant to SP-D and MBL.…”

“…Since their appearance in the human population in 1968, H3N2 subtype viruses have shown a progressive increase in N-linked glycosylation (24,25) and recently circulating strains generally carry six to seven potential sites in the globular head region of HA. Recent seasonal H1N1 viruses carry four to five N-glycosylation sequons on the head of HA (25,26) compared with the prototypic 1918 H1N1 pandemic strain A/ South Carolina/1/18 (SC18), which carried a single site (27). Previous studies have shown that increased glycosylation of H3 subtype viruses correlated with enhanced susceptibility to rodent SP-D and MBL and reduced virulence in mice (15,28), although highly glycosylated viruses could elicit severe disease in SP-Ddeficient mice (28).…”

Crystal structure of the swine-origin A (H1N1)-2009 influenza A virus hemagglutinin (HA) reveals similar antigenicity to that of the 1918 pandemic virus

“…Current S-OIV (2009 H1N1 influenza virus) is a triple reassortment (in terms of host-origin) of influenza gene segments, with PA and PB2 from avian, PB1 from human and HA, NP, NS, NA and M from classical/Eurasian swine (Dawood et al, 2009;Smith et al, 2009;Gao and Sun, 2010). This current H1N1 virus has been found to have many similar properties to the 1918 pandemic H1N1 virus, including the overall similarity of the genome and characteristics of pathogenesis (Itoh et al, 2009;Shen et al, 2009;WHO, 2009;Yang et al, 2009;Igarashi et al, 2010;Yeping Sun et al, 2010).…”