Changes in the hemagglutinin of H5N1 viruses during human infection--influence on receptor binding.
As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans of current H5N1 viruses only requires a few genetic changes. An essential step is alteration of the virus hemagglutinin from preferential binding to avian receptors for the recognition of human receptors present in the upper airway. We have identified receptor-binding changes which emerged during H5N1 infection of humans, due to single amino acid substitutions, Ala134Val and Ile151Phe, in the hemagglutinin. Detailed biological, receptor-binding, and structural analyses revealed reduced binding of the mutated viruses to avian-like receptors, but without commensurate increased binding to the human-like receptors investigated, possibly reflecting a receptor-binding phenotype intermediate in adaptation to more human-like characteristics. These observations emphasize that evolution in nature of avian H5N1 viruses to efficient binding of human receptors is a complex multistep process.
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Martin
M
Crusat
Junfeng
J
Liu
Angelina S
AS
Palma
Robert A
RA
Childs
Yan
Y
Liu
Stephen A
SA
Wharton
Yi Pu
YP
Lin
Peter J
PJ
Coombs
Stephen R
SR
Martin
Mikhail
M
Matrosovich
Zi
Z
Chen
David J
DJ
Stevens
Vo Minh
VM
Hien
Tran Tan
TT
Thanh
Le Nguyen Truc
le NT
Nhu
Lam Anh
LA
Nguyet
Do Quang
do Q
Ha
H Rogier
HR
van Doorn
Tran Tinh
TT
Hien
Harald S
HS
Conradt
Makoto
M
Kiso
Steve J
SJ
Gamblin
Wengang
W
Chai
John J
JJ
Skehel
Alan J
AJ
Hay
Jeremy
J
Farrar
Menno D
MD
de Jong
Ten
T
Feizi
D000818:Animals; D018360:Crystallography, X-Ray; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D005585:Influenza in Birds / Q000821:virology; D007251:Influenza, Human / Q000821:virology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011200:Poultry; D011485:Protein Binding; D011487:Protein Conformation; D012367:RNA, Viral / Q000235:genetics; D011991:Receptors, Virus / Q000378:metabolism; D017422:Sequence Analysis, DNA; D053585:Virus Attachment
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D050505:Mutant Proteins; D012367:RNA, Viral; D011991:Receptors, Virus; C109963:hemagglutinin, avian influenza A virus
Biolayer interferometry; Carbohydrate microarray; H5N1 influenza infection; Hemagglutination assays; Hemagglutinin; Hemagglutinin X-ray crystal structure; Pyrosequencing; Receptor binding; Receptor specificity; Synthetic sialylglycopolymers