H5N1 receptor specificity as a factor in pandemic risk

Abstract

The high pathogenicity of H5N1 viruses in sporadic infections of humans has raised concerns for its potential to acquire the ability to transmit between humans and emerge as a highly pathogenic pandemic virus. Because avian and human influenza viruses differ in their specificity for recognition of their host cell receptors, receptor specificity represents one barrier for efficient transmission of avian viruses in human hosts. Over the last century, each influenza virus pandemic has coincided with the emergence of virus with an immunologically distinct hemagglutinin exhibiting a ‘human-type’ receptor specificity, distinct from that of viruses with the same hemagglutinin circulating in zoonotic species. Recent studies suggest that it is possible for H5N1 to acquire human type receptor specificity, but this has not occurred in nature. This review covers what is known about the molecular basis for the switch between avian and human-type receptor specificity for influenza viruses that have successfully adapted to man, the potential for H5N1 to evolve to human-type receptor specificity and its relevance to pandemic risk.

H1N1 Swine Influenza Viruses Differ from Avian Precursors by a Higher pH Optimum of Membrane Fusion

“…Whereas receptor-binding specificity of influenza virus HA is a well-known factor determining viral host range (8)(9)(10)(11), the role of the fusion-promotion characteristics of the HA in host range restriction is less well understood (17,19). The pioneering studies of Scholtissek showed that stability of influenza viruses at low pH correlated, at least partially, with the viral host species (27,54), implying that host-specific differences exist between the viruses in the pH optimum of HA conformational stability.…”

A Unique and Conserved Neutralization Epitope in H5N1 Influenza Viruses Identified by an Antibody against the A/Goose/Guangdong/1/96 Hemagglutinin

“…1A). The loss of glycosylation at N158 in recently emerged H5N1 strains has been associated with increased potential to acquire a receptor specificity that supports aerosol transmission in ferrets (27,28). However, loss of this glycan alone is not sufficient to change receptor specificity, since GD1 exhibits strong binding to ␣2-3 sialosides that are characteristic of avian virus receptor specificity (Fig.…”

Hemagglutinin Receptor Specificity and Structural Analyses of Respiratory Droplet-Transmissible H5N1 Viruses

“…Avian viruses, like H5N1, preferentially bind to ␣2-3 sialosides (avian-type receptors), whereas human viruses prefer ␣2-6 sialosides (human-type receptors that are found in the human respiratory tract). The three influenza A virus serotypes that have circulated in humans to date (H1N1, H2N2, and H3N2) are believed to have evolved from avian origin and to have acquired the ability to recognize ␣2-6 sialosides through minimal mutations in the receptor binding pocket of the HA (5,6). Since binding to ␣2-6 sialosides is believed to be vital for efficient transmission between humans, there has been a major effort to define how H5N1 viruses could acquire this ability (6,7).…”

“…Glycan array analysis has become a standard assay to assess influenza A virus receptor specificity (6,11,12), since it probes numerous biologically important glycans within a single assay. Glycan array analysis is a qualitative assay, and it has been shown that graded dilution of the binding protein reduces the signal without significantly altering the relative levels of binding to different glycans (13).…”