Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses.

Johanna West¹ Juliane Röder¹ Tatyana Matrosovich¹ Jana Beicht¹ Jan Baumann¹ Nancy Mounogou Kouassi¹ Jennifer Doedt¹ Nicolai Bovin² Gianpiero Zamperin³ Michele Gastaldelli³ Annalisa Salviato³ Francesco Bonfante³ Sergei Kosakovsky Pond⁴ Sander Herfst⁵ Ron Fouchier⁵ Jochen Wilhelm⁶ Hans-Dieter Klenk¹ Mikhail Matrosovich¹

Affiliations 6 institutions

Institute of Virology, Philipps University, Marburg, Germany.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia.
Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy.
Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania, United States of America.
Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands.
Institute of Lung Health (ILH), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.

PMID34555124 DOI10.1371/journal.ppat.1009566 Year2021 Journal PLoS pathogens PLoS Pathog Languageeng Publication statusActive

Active Last checked 2026-10-04 03:30:36 Source: NCBI PubMed

Abstract

The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.

Supporting text Virus Host Location

Animals 1981 Ducks 86 Hemagglutinin Glycoproteins, Influenza Virus 183 Humans 1455 Influenza A Virus, H3N2 Subtype 49 Influenza in Birds 352 Influenza, Human 290 Pandemics 109 Viral Zoonoses 66

Evidence records

4 total

Functional Mechanism

4 records · 2 evidence types

Evidence type Receptor Usage

1 records

OVE5169 Receptor Usage

Key finding

The avian precursor hemagglutinin exhibited a receptor binding profile typical for duck influenza A viruses, indicating avian-type receptor usage.

Virus

Host

Location

Supporting text

The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs.

Method: receptor binding assay | hemagglutinin functional analysis
Receptors: avian-type sialic acid receptors

Evidence type Molecular Adaptation

3 records

OVE5168 Molecular Adaptation

Key finding

Substitutions D63N and D81N with addition of N‑glycans in the hemagglutinin of avian H3 viruses are common markers of adaptation to mammalian hosts.

Virus

Host

Location

Supporting text

Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals.

Genes or proteins: hemagglutinin | HA
Mutations: D63N | D81N
Mechanism types: host-range expansion

OVE5167 Molecular Adaptation

Key finding

Hemagglutinin substitutions R62I, D81N, and A144G enhanced replication of A/Hong Kong/1/1968 virus in human airway epithelial cultures, indicating molecular adaptation to human host cells.

Virus

Host

Location

Supporting text

Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures.

Genes or proteins: hemagglutinin | HA
Host factors: human airway epithelial cultures
Mutations: R62I | D81N | A144G
Mechanism types: replication adaptation | host-range expansion

OVE5166 Molecular Adaptation

Key finding

Hemagglutinin substitutions Q226L and G228S in A/Hong Kong/1/1968 virus altered receptor specificity and replication and decreased HA stability, demonstrating adaptation related to receptor binding and replication in human cells.

Virus

Host

Location

Supporting text

Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability.

Genes or proteins: hemagglutinin | HA
Receptors: receptor specificity
Mutations: Q226L | G228S
Mechanism types: receptor binding | replication adaptation

References

95 references

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Evidence overview

Evidence 4

Categories 1

Types 2

Virus 3

Host 1

Country 0

Host context

Experimental system 1

Evidence categories

Linked entities

Viruses

Hosts

ducks Anas

Locations

Publication metadata

Journal: PLoS pathogens
Volume / Issue / Pages: 17 / 9 / e1009566
ISSN: 1553-7374
Journal country: United States
DOI: 10.1371/journal.ppat.1009566