Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway

Abstract

ABSTRACTInfluenza A viruses are able to adapt to restrictive conditions due to their high mutation rates. Here, we addressed the question by which mechanisms influenza A viruses may escape restriction by the cellular importin-α7 protein, a component of the nuclear import machinery required for avian-mammalian adaptation and replicative fitness in human cells. Therefore, we assessed viral evolution in mice lacking the importin-α7 gene. Here, we show that particularly three mutations occur with high frequency in the viral NP protein (G102R, M105K and D375N) in a specific structural area uponin vivoadaptation. Moreover, our findings suggest that the adaptive NP mutations mediate viral escape from importin-α7 requirement likely due to the utilization of alternative interaction sites in NP beyond the classical nuclear localization signal and importin-α isoforms. However, viral escape from importin-α7 is, at least in part, associated with reduced replicative fitness in human cells.