Antigenic drift in the evolution of H1N1 influenza A viruses resulting from deletion of a single amino acid in the haemagglutinin gene

Abstract

Two genetically distinct lineages of H1N1 influenza A viruses, circulated worldwide before 1994, were antigenically indistinguishable. In 1994, viruses emerged in China, including A/Beijing/262/ 95, with profound antigenic differences from the contemporary circulating H1N1 strains. Haemagglutinin sequence comparisons of either a predecessor virus, A/Hebei/52/94, or one representative of the cocirculating A/Bayern/7/95-like clade, A/Shenzhen/227/95, revealed a deletion of K at position 134 (H3 numbering) in the antigenic variants. The K134 deletion conferred a selective advantage to the Chinese deletion lineage, such that it eventually gave rise to currently circulating H1 viruses. Using reverse genetics to generate viruses with either an insertion or deletion of aa 134, we have confirmed that the K134 deletion, rather than a constellation of sublineage specific amino acid changes, was sufficient for the antigenic difference observed in the Chinese deletion lineage, and reinsertion of K134 revealed the requirement of a compatible neuraminidase surface glycoprotein for viral growth.Approximately 20 % of the world's population is infected by influenza A each year, resulting in significant mortality and morbidity (Stohr, 2002). The high incidence of influenza cases is attributable to the ability of the influenza virus to escape immunity induced by prior infection or vaccination. This escape is potentiated by the accumulation of mutations in the surface glycoproteins haemagglutinin (HA), and to a lesser extent neuraminidase (NA), which confer antigenic change to the virus. This phenomenon, known as antigenic drift, necessitates annual vaccine updates to confer protection against the currently circulating strains.Mutations in the HA molecule are considered to contribute almost entirely to the antigenic drift observed among influenza A viruses (Wilson & Cox, 1990). Those sites at the distal tip of the H1 HA molecule and on the side of the globular head near the receptor-binding pocket appear to be the main targets of the human immune response (Cox & Brokstad, 1999;Raymond et al., 1986;Sato et al., 2004). Influenza A viruses bind to sialic acids on the surface of target cells via a depression in the distal surface of the globular head of the HA molecule (Weis et al., 1988;Wilson et al., 1981). Several residues within this depression are highly conserved across the HA subtypes, including residues 98, 134, 138, 153 and 183 (H3 numbering) (Nobusawa et al., 1991). Amino acid substitutions within the receptor-binding pocket or the 'second shell' residues, including 190, 225 and 158, may alter the specificity toward certain types of galactosidic linkages, namely a2-6Gal or a2-3Gal linkages (Aytay & Schulze, 1991; Matrosovich et al., 2000). Because of its location on the HA threedimensional structure, mutations in the receptor-binding pocket or second shell residues can alter the antigenicity of a virus in addition to, or instead of, modifying receptor specificity or affinity (Daniels et al., 1984).The HA1 domains of the HA g...

Sialylneolacto-N-tetraose c (LSTc)-bearing Liposomal Decoys Capture Influenza A Virus

“…X31 and Philippines are each mouse-adapted reassortant strains. Beijing 262/95 is a relatively recent human clinical isolate that resembles modern H1N1 variants that emerged after 1994 (48) and has undergone relatively little selection in the laboratory. One might expect that the Beijing human isolate would be most greatly inhibited by LSTc decoy liposomes given its adaptation to the human airway, which has a high prevalence of ␣2-6-linked SA (49).…”

A sparse hierarchical Bayesian model for detecting relevant antigenic sites in virus evolution

“…Additional residues have also been identified on the SAT serotypes (Crowther et al 1993b;Grazioli et al 2006), as well as others on related serotypes A, O, C and Asia1 which may also occur within the SAT serotypes (Grazioli et al 2013;Kitson et al 1990;Lea et al 1994;Saiz et al 1991). For the H1N1 virus, experimental studies have identified four major antigenic sites (Caton et al 1982), as well as a number of other sites known to be important (McDonald et al 2007).…”

Immune Escape Variants of H9N2 Influenza Viruses Containing Deletions at the Hemagglutinin Receptor Binding Site Retain Fitness In Vivo and Display Enhanced Zoonotic Characteristics

“…Both natural immunity and vaccine-induced immunity are mediated primarily through antibodies against HA, in particular neutralizing antibodies that block the receptor binding ability of HA (25). In response to immune pressure exerted by neutralizing antibodies, viruses are able to “escape” through the accumulation of amino acid substitutions or, more rarely observed, amino acid deletions (26, 27). …”