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Characterization of H5N1 influenza virus variants with hemagglutinin mutations isolated from patients.

Yohei Watanabe1 Yasuha Arai2 Tomo Daidoji3 Norihito Kawashita Madiha S Ibrahim4 Emad El-Din M El-Gendy4 Hiroaki Hiramatsu5 Ritsuko Kubota-Koketsu6 Tatsuya Takagi Takeomi Murata7 Kazuo Takahashi8 Yoshinobu Okuno6 Takaaki Nakaya3 Yasuo Suzuki5 Kazuyoshi Ikuta2
Affiliations 8 institutions
  1. [email protected].
  2. Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  3. Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  4. Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
  5. Health Scientific Hills, College of Life and Health Sciences, Chubu University, Aichi, Japan.
  6. Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, Japan.
  7. Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka, Japan.
  8. Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka, Japan.
PMID 25852160 2015 mBio eng epublish
PubMed DOI Browse context

Article

Publication summary

A change in viral hemagglutinin (HA) receptor binding specificity from α2,3- to α2,6-linked sialic acid is necessary for highly pathogenic avian influenza (AI) virus subtype H5N1 to become pandemic. However, details of the human-adaptive change in the H5N1 virus remain unknown. Our database search of H5N1 clade 2.2.1 viruses circulating in Egypt identified multiple HA mutations that had been selected in infected patients. Using reverse genetics, we found that increases in both human receptor specificity and the HA pH threshold for membrane fusion were necessary to facilitate replication of the virus variants in human airway epithelia. Furthermore, variants with enhanced replication in human cells had decreased HA stability, apparently to compensate for the changes in viral receptor specificity and membrane fusion activity. Our findings showed that H5N1 viruses could rapidly adapt to growth in the human airway microenvironment by altering their HA properties in infected patients and provided new insights into the human-adaptive mechanisms of AI viruses. Circulation between bird and human hosts may allow H5N1 viruses to acquire amino acid changes that increase fitness for human infections. However, human-adaptive changes in H5N1 viruses have not been adequately investigated. In this study, we found that multiple HA mutations were actually selected in H5N1-infected patients and that H5N1 variants with some of these HA mutations had increased human-type receptor specificity and increased HA membrane fusion activity, both of which are advantageous for viral replication in human airway epithelia. Furthermore, HA mutants selected during viral replication in patients were likely to have less HA stability, apparently as a compensatory mechanism. These results begin to clarify the picture of the H5N1 human-adaptive mechanism.

Genetic Variation Mutation, Missense Adaptation, Biological Animals Cells, Cultured Disease Models, Animal Epithelial Cells Hemagglutinin Glycoproteins, Influenza Virus Humans Influenza A Virus, H5N1 Subtype Influenza, Human Mice, Inbred BALB C Orthomyxoviridae Infections Survival Analysis hemagglutinin, avian influenza A virus

Structured evidence records

Evidence records

3 total
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.80
Key finding

H5N1 viruses from Egyptian patients showed multiple hemagglutinin mutations selected during human infection, reflecting genomic adaptation to the human host.

Virus
IAV H5N1
Location
Not specified
Supporting text

Our database search of H5N1 clade 2.2.1 viruses circulating in Egypt identified multiple HA mutations that had been selected in infected patients.

Genes or proteins
hemagglutinin; HA
Analysis methods
sequence database search
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 1.00
Key finding

H5N1 influenza virus variants with hemagglutinin mutations exhibited increased binding to human-type α2,6-linked sialic acid receptors and altered HA fusion properties that enhanced replication in human airway epithelial cells, representing molecular adaptation to human hosts.

Virus
IAV H5N1
Host
Not specified
Location
Not specified
Supporting text

Using reverse genetics, we found that increases in both human receptor specificity and the HA pH threshold for membrane fusion were necessary to facilitate replication of the virus variants in human airway epithelia. Furthermore, variants with enhanced replication in human cells had decreased HA stability, apparently to compensate for the changes in viral receptor specificity and membrane fusion activity.

Genes or proteins
hemagglutinin; HA
Receptors
α2,6-linked sialic acid
Mechanism types
receptor_binding; cell_entry; replication_efficiency; host_adaptation
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

HA mutations in H5N1 influenza virus variants selected in infected patients increased receptor binding specificity toward α2,6-linked sialic acid, enhancing replication in human airway epithelial cells.

Virus
IAV H5N1
Location
Not specified
Supporting text

A change in viral hemagglutinin (HA) receptor binding specificity from α2,3- to α2,6-linked sialic acid is necessary for highly pathogenic avian influenza virus subtype H5N1 to become pandemic. Using reverse genetics, we found that increases in both human receptor specificity and the HA pH threshold for membrane fusion were necessary to facilitate replication of the virus variants in human airway epithelia.

Method
reverse genetics
Receptors
α2,6-linked sialic acid