Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence.

We generated influenza A viruses expressing mutant NS1 proteins unable to activate phosphoinositide 3-kinase (PI3K) in two mouse-lethal strains. The recombinant A/Puerto Rico/8/34 (rPR8) mutant virus strain was attenuated and caused reduced morbidity/mortality. For the recombinant A/WSN/33 (rWSN) virus strain, the inability to stimulate PI3K had minimal impact on replication or morbidity/mortality. Cell-based assays revealed subtly distinct intracellular sites of NS1 localization and PI3K activation between the strains. We hypothesize that specific spatially regulated NS1-activated PI3K signaling, rather than simply the total level of active PI3K, is important for virus replication and virulence.