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Furthermore, alterations at position 231 determine a carboxy-terminal extension of seven amino acids from 230 to 237 residues. Sequence analyses of NS1 of the last 90\u2009years suggest that variations at these two positions are functionally linked. To determine the impact of the two positions on viral replication<jats:italic>in vivo<\/jats:italic>, we used a mouse-adapted variant of A\/Hong Kong\/01\/68 (maHK68) (H3N2). maHK68 encodes an NS1 of 237 amino acids with lysine at position 196. A panel of recombinant maHK68 viruses was generated encoding NS1 variants that differed at positions 196 and 231. Our analyses showed a clear effect of the K-196-to-E exchange on interferon induction and virus virulence. These effects were further modulated by the loss of the seven-amino-acid extension. We propose that the combination of NS1 E-196 with the short C-terminal variant conferred a fitness advantage that is reflected by increased virulence<jats:italic>in vivo<\/jats:italic>. 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