Differential sensitivity of human, avian, and equine influenza A viruses to a glycoprotein inhibitor of infection: selection of receptor specific variants

Abstract Human and animal (avian and equine) influenza A virus isolates of the H3 serotype exhibit marked differences in their ability to bind specific sialyloligosaccharide sequences that serve as cell surface receptor determinants. ( G. Rogers and J. Paulson, 1983 , Virology 127 , 361–373). Whereas human isolates of this subtype strongly agglutinate enzymatically modified human erythrocytes containign the terminal SAα2,6Gal sequence, avian and equine isolates preferentially agglutinate erythrocytes bearing the SAα2,3Gal sequence. As shown in this report, a glycoprotein found in horse serum, α 2 -macroglobulin, is a potent inhibitor of viral adsorption to the cell surface for human H3 isolates. In contrast, avian and equine isolates are poorly inhibited suggesting a correlation between receptor specificity and inhibitor sensitivity. Growth of a human H3 isolate (A/Memphis/102/72) on MDCK cells in the presence of horse serum resulted in an overall shift in the virus receptor specificity from preferential binding of the SAα2,6Gal linkage to preferential binding of the SAα2,3Gal linkage characteristic of avian and equine isolates. Clonally isolated variants of A/Memphis/102/72 grown in the presence or absence of horse serum exhibited binding properties that account for those observed in the file disolates. Clones which preferentially bound the SAα2,6Gal linkage, like the parent human virus, were very sensitive to inhibition of hemagglutination by horse serum and equine α 2 -macroglobulin. In contrast, receptor variants which preferentially bound the SAα2,3Gal linkage, like the avian and equine isolate, were insensitive to such inhibitors. None of the variants was very sensitivie to inhibition of hemagglutination by human α 2 -macroglobulin. These results suggest that the presence, in vivo , of a glycoprotein inhibitor such as equine α 2 -macroglobulin could suppress infection of influenza viruses bearing an H3 hemagglutinin with a SAα2,6Gal specific, inhibitor sensitive phenotype, allowing gorwth to predominance of a virus which is SAα2,3Gal specific and inhibitor insensitive as found in avian and equine isolates.