Avian-virus-like receptor specificity of the hemagglutinin impedes influenza virus replication in cultures of human airway epithelium.
A non-optimal receptor-binding specificity of avian influenza viruses is believed to hamper their replication in humans; however, the magnitude of this restriction remains undefined. Here we generated recombinant viruses, R1 and R2, that differed solely by two amino acids in the receptor-binding site of their hemagglutinin (HA). R1 harbored the original HA of the pandemic human virus A/Hong Kong/1/68 (H3N2), whereas R2 was the L226Q/S228G HA mutant with avian-virus-like receptor specificity. In differentiated cultures of human tracheo-bronchial epithelial cells, R1 preferentially infected non-ciliated cells, whereas R2 predominantly infected ciliated cells indicating that cell tropism was determined by the viral receptor specificity. In the course of multi-cycle replication in these cultures, R2 spread less efficiently and grew to 2-10-fold lower titers than did R1. These results for the first time estimate the level of receptor-dependent restriction of avian influenza viruses in human airway epithelium. They support a theory that alteration of the receptor specificity of an avian virus could facilitate its human-to-human transmission.
Matrosovich
Mikhail
M
Institute of Virology, Philipps University, 35043 Marburg, Germany. Mikhail.Matrosovich@nimr.mrc.ac.uk
Matrosovich
Tatyana
T
Uhlendorff
Jennifer
J
Garten
Wolfgang
W
Klenk
Hans-Dieter
HD
D000956:Antigens, Viral / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity / Q000502:physiology*; D007251:Influenza, Human / Q000821:virology*; D009154:Mutation; D019158:N-Acetylneuraminic Acid; D011991:Receptors, Virus / Q000502:physiology*; D020545:Respiratory Mucosa / Q000821:virology; D013045:Species Specificity; D014779:Virus Replication
D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; C109963:hemagglutinin, avian influenza A virus; D019158:N-Acetylneuraminic Acid