Mechanisms of resistance of influenza virus to neuraminidase inhibitors

Abstract

Structure-based inhibitor design has resulted in the development of highly selective inhibitors of the influenza virus neuraminidase (NA). So far, two compounds have been approved for therapeutic use, zanamivir and oseltamivir, but others are under development. However, it is important to establish whether resistance arises readily to these new inhibitors. Unlike amantadine, it takes several passages in culture before resistant variants are isolated. Mutants have also been isolated from oseltamivir-treated patients and from an immunocompromised zanamivir-treated child. Mutations are found in both the NA and the hemagglutinin (HA). In vitro two HA or an HA and NA mutation can act synergistically to increase resistance. The NA mutations are in previously conserved catalytic and structural residues, Glu 119, Arg 152, Arg 292, and His 274. The NA mutations have an adverse effect on NA activity or stability. There are significant quantitative differences observed between the inhibitors upon binding to these mutant NAs. The HA mutations tend to map to regions associated with receptor binding of the HA. The effect of the HA mutations appears to be to reduce the affinity of the HA for the cellular receptor. Their role in vivo is not yet known.