Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.
Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 'bird flu' and the H1N1 'Spanish flu'. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.
Sui
Jianhua
J
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street JFB 826, Boston, Massachusetts 02115, USA. jianhua_sui@dfci.harvard.edu
Hwang
William C
WC
Perez
Sandra
S
Wei
Ge
G
Aird
Daniel
D
Chen
Li-mei
LM
Santelli
Eugenio
E
Stec
Boguslaw
B
Cadwell
Greg
G
Ali
Maryam
M
Wan
Hongquan
H
Murakami
Akikazu
A
Yammanuru
Anuradha
A
Han
Thomas
T
Cox
Nancy J
NJ
Bankston
Laurie A
LA
Donis
Ruben O
RO
Liddington
Robert C
RC
Marasco
Wayne A
WA
D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000737:chemistry* / Q000276:immunology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control; D019151:Peptide Library; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D016019:Survival Analysis; D053586:Virus Internalization / Q000187:drug effects*
D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D019151:Peptide Library; C109963:hemagglutinin, avian influenza A virus