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Abstract zur Publikation: Virulence determinants of avian H5N1 influenza A virus in mammalian and avian hosts: The role of the C-terminal ESEV motif in the viral NS1 protein

Zielecki F, Semmler I, Kalthoff D, Voss D, Mauel S, Gruber AD, Beer M, Wolff T (2010): Virulence determinants of avian H5N1 influenza A virus in mammalian and avian hosts: The role of the C-terminal ESEV motif in the viral NS1 protein.
J. Virol. 84 (20): 10708-10718. Epub Aug 4.

We assessed the prediction that access of the viral NS1 protein to cellular PDZ domain protein networks enhances the virulence of highly pathogenic avian influenza A virus. The NS1 proteins of most avian influenza viruses bear the C-terminal ligand sequence Glu-Ser-Glu-Val (ESEV) for PDZ domains present in multiple host proteins, whereas such a motif is not found in the NS1 homologues of seasonal human virus strains. Previous analysis showed that a C-terminal ESEV motif increases viral virulence when introduced into the NS1 protein of mouse–adapted H1N1 influenza virus. To examine the role of the PDZ domain ligand motif in avian influenza virus virulence we generated three recombinants derived from the prototypic H5N1 influenza A/Vietnam/1203/04 virus expressing NS1 proteins either with the C-terminal ESEV or the human RSKV consensus, or bearing a natural truncation of this motif, respectively. Cell biological analyses showed a strong control of NS1 nuclear migration in infected mammalian and avian cells with only minor differences between the three variants. The ESEV sequence attenuated viral replication on cultured human, murine and duck cells, but not on chicken fibroblasts. However, all three viruses caused highly lethal infections in mice and chickens with little differences in viral organ titers and their mean lethal dose or intravenous pathogenicity index, respectively. These findings demonstrate that a PDZ domain ligand sequence in NS1 contributes little to the virulence of H5N1 virus in these hosts and indicates that this motif modulates viral replication in a strain- and host-dependent manner.

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