Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance

Influenza Escape Tricks Tamiflu, or oseltamivir, has been extensively stockpiled by several governments in anticipation of a dangerous influenza pandemic. So far, its large-scale use has not been required, but, despite this, resistance has emerged in seasonal strains mediated by a single point mutation of histidine to tyrosine in the 274 residue (H274Y) of neuraminidase. When the resistant virus was first discovered in 1998, it grew poorly, but by 2008 the virus was reinvigorated and the mutation had spread worldwide in seasonal influenza. So what happened that improved viral fitness so radically? Bloom et al. (p. 1272 ; see the Perspective by Holmes ) show that the H274Y mutation hinders the folding of the neuraminidase enzyme. In the more vigorous recent oseltamivir-resistant isolates, other mutations compensate for the deleterious effect of H274Y and restore fitness to the virus.