The effect of adaptive mutations in the influenza A NS1 protein on CPSF30 and PABP1 binding

Abstract

The Influenza A NS1 protein is an interferon (IFN) antagonist and a major virulence determinant. To characterize the genetic basis of NS1-mediated virulence, highly pathogenic mouse-adapted Influenza A strains were derived from human A/Hong Kong/1/68 H3N2 by experimental evolution in the mouse lung. Within these strains seven specific NS1 mutations were identified, some of which conferred greater IFN resistance and/or increased viral protein synthesis to the virus. Most of these mutations were shown to affect NS1 CPSF30 binding, which may affect post-transcriptional processing and increase host IFN induction. Some of these mutations were also shown to increase NS1 binding to host translation initiation factor PABP1, supporting a model of increased IFN resistance through direct modulation of host translation.