Genetic analysis reveals that both haemagglutinin and neuraminidase determine the sensitivity of naturally occurring avian influenza viruses to zanamivir in vitro

The basis of differential sensitivity of replication of influenza Viruses to the neuraminidase-specific inhibitor zanamivir was examined using four avian influenza viruses and reassortants produced between them. IC50 values for inhibition of neuraminidase activity by zanamivir were similar for each of the four viruses, whereas the haemagglutinating activity of each of the viruses was relatively insensitive to zanamivir. However, the four viruses showed distinct zanamivir-sensitivity profiles in tissue culture. Analysis of the reassortant viruses showed that sensitivity was determined by the haemagglutinin gene (segment 4) and the neuraminidase gene (segment 6) and was independent of the remaining six RNA segments. Decreased sensitivity to zanamivir was associated with possession of a haemagglutinin that is released from cells with decreased dependence on neuraminidase and with possession of a neuraminidase that has a short stalk region. (C) 1999 Academic Press.