Abstract

Since 2007, highly pathogenic clade 2.3.2 H5N1 avian influenza A (A(H5N1)) viruses have evolved to clade 2.3.2.1a, b, and c; currently only 2.3.2.1c A(H5N1) viruses circulate in wild birds and poultry. During antigenic evolution, clade 2.3.2.1a and c A(H5N1) viruses acquired both S144N and V223I mutations around the receptor binding site of hemagglutinin (HA), with S144N generating an N-glycosylation sequon. We introduced single or combined reverse mutations, N144S and/or I223V, into the HA gene of the clade 2.3.2.1c A(H5N1) virus and generated PR8-derived, 2 + 6 recombinant A(H5N1) viruses. When we compared replication efficiency in embryonated chicken eggs, mammalian cells, and mice, the recombinant virus containing both N144S and I223V mutations showed increased replication efficiency in avian and mammalian hosts and pathogenicity in mice. The N144S mutation significantly decreased avian receptor affinity and egg white inhibition, but not all mutations increased mammalian receptor affinity. Interestingly, the combined reverse mutations dramatically increased the thermostability of HA. Therefore, the adaptive mutations possibly acquired to evade avian immunity may decrease viral thermostability as well as mammalian pathogenicity.

Highlights

  • Pathogenic H5N1 avian influenza A (HP A(H5N1)) viruses are fatal to poultry and cause high human fatality after dead-end transmission from infected poultry [1,2]

  • The receptor binding site (RBS) on the globular head of HA is a shallow pocket-like structure consisting of three secondary structure elements (130-loop, 190-helix, and 220-loop) and a base (Y98, W153, H183, and Y195 in H3 numbering) [12]

  • All the amino acid sequences of HA proteins of clade 2.3.2 and clade 2.3.2.1 strains in the databases were compared, and we found variations at 144NGS and 158NGS and at amino acid residue 223 around the RBS (Table 2)

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Summary

Introduction

Pathogenic H5N1 avian influenza A (HP A(H5N1)) viruses are fatal to poultry and cause high human fatality after dead-end transmission from infected poultry [1,2]. Virus A/goose/Guangdong/1/96 (clade 0) has evolved into multiple clades from clade 1 to 9 [5]. Viruses 2019, 11, 923 clade 2.3.2 viruses evolved into clade 2.3.2.1 and further diversified into 2.3.2.1a, b, and c in 2009 [6,7]. Hemagglutinin (HA) is a surface glycoprotein exposed on the outside of virus particles and it forms a noncovalent homotrimer composed of a distal globular head and proximal stalk [12]. HA binds to cell surface receptors to infect the host cell, and avian and human influenza A viruses (IAVs) preferentially bind to sialic acid α2,3-linked (α2,3 SA)

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