Highly pathogenic avian influenza viruses (HPAIV) with reassorted NS segments from H5-and H7-type avian virus strains placed in the genetic background of the A/FPV/Rostock/34 HPAIV (FPV; H7N1) were generated by reverse genetics. Virological characterizations demonstrated that the growth kinetics of the reassortant viruses differed from that of wild-type (wt) FPV and depended on whether cells were of mammalian or avian origin. Surprisingly, molecular analysis revealed that the different reassortant NS segments were not only responsible for alterations in the antiviral host response but also affected viral genome replication and transcription as well as nuclear ribonucleoprotein (RNP) export. RNP reconstitution experiments demonstrated that the effects on accumulation levels of viral RNA species were dependent on the specific NS segment as well as on the genetic background of the RNA-dependent RNA polymerase (RdRp). Beta interferon (IFN-␤) expression and the induction of apoptosis were found to be inversely correlated with the magnitude of viral growth, while the NS allele, virus subtype, and nonstructural protein NS1 expression levels showed no correlation. Thus, these results demonstrate that the origin of the NS segment can have a dramatic effect on the replication efficiency and host range of HPAIV. Overall, our data suggest that the propagation of NS reassortant influenza viruses is affected at multiple steps of the viral life cycle as a result of the different effects of the NS1 protein on multiple viral and host functions.Since 1997, the emergence of a new H5N1 highly pathogenic avian influenza virus (HPAIV) has resulted in major losses to the poultry industry and caused over 460 human infections with approximately 60% mortality (12, 55). The virus first appeared in Asia but has now spread to many countries throughout Europe and Africa with the potential to cause a worldwide pandemic. H7-type HPAIV strains have caused outbreaks in Europe for many years and have resulted in some infections in humans, albeit with low mortality rates (18). With the rapid spread of H5N1 viruses to Europe, it is increasingly likely that H5-type viruses may reassort with H7-type HPAIV. We have previously shown that the NS segment of an H5N1 virus isolated in 1996 increased the replication and pathogenicity of an H7-type HPAIV (26) and were therefore interested in investigating the effect of other NS segments to determine how NS segments encoded by different H7 and H5 subtype viruses affect the virulence of an H7-type HPAIV. We were also interested in the effect of an NS segment from an H5N1 virus isolated after 1998, as it has previously been reported that the NS segment of such viruses cause enhanced replication in mammalian cells (52).

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