Abstract

We hypothesise that some influenza virus adaptations to poultry may explain why the barrier for human-to-human transmission is not easily overcome once the virus has crossed from wild birds to chickens. Since the cluster of human infections with H5N1 influenza in Hong Kong in 1997, chickens have been recognized as the major source of avian influenza virus infection in humans. Although often severe, these infections have been limited in their subsequent human-to-human transmission, and the feared H5N1 pandemic has not yet occurred. Here we examine virus adaptations selected for during replication in chickens and other gallinaceous poultry. These include altered receptor binding and increased pH of fusion of the haemagglutinin as well as stalk deletions of the neuraminidase protein. This knowledge could aid the delivery of vaccines and increase our ability to prioritize research efforts on those viruses from the diverse array of avian influenza viruses that have greatest human pandemic potential. Also watch the Video Abstract.

Highlights

  • Avian influenza viruses do not readily infect humans because of the host range barriers that restrict them at a number of stages of their replication and transmission cycle [1]

  • We recently showed that in ferrets, an otherwise transmissible pH1N1 2009 virus lost the transmissible phenotype when it encoded a NA derived from an H5N1 virus naturally truncated by 20 amino acids, and this block was overcome by extending the NA stalk length back to that seen in human-adapted viruses [90]

  • Adaptation of influenza A viruses in poultry selects for HAs with additional glycosylation sites that impair human receptor binding; it selects for increased pH of fusion that results in environmental fragility, and NA stalk length truncation that impairs the virus’ ability to overcome the mucus barrier (Figs. 1, 2, and 3)

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Summary

Introduction

Avian influenza viruses do not readily infect humans because of the host range barriers that restrict them at a number of stages of their replication and transmission cycle [1]. It should be noted that, as H5N1 virus continues to circulate widely amongst avian species, some natural isolates of H5N1 virus that already lack glycosylation at HA residues 158–160 have been reported in Egypt, demonstrating that this potential host range barrier is rather readily lost [54, 55] Taken together these observations suggest that, during outbreaks of avian influenza viruses in poultry, HA sustains mutations that affect receptor binding, and some of these may sterically hinder the virus host interaction in ways presumably advantageous for poultry but deleterious for transmission between humans. Other mutations that enhance binding to human receptors are not on their own sufficient to enable transformation into a human transmissible virus [53, 56]

The pH stability of HA affects both virulence and transmission
The cost of instability
Deletions in the neuraminidase stalk attenuate influenza virus in humans
Conclusions and outlook
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