: Viral products that interact with host components and that suppress host defense mechanisms are considered important virulence factors. Recently it was shown that the nonstructural protein (NS1) of influenza A virus plays a role in overcoming the type I interferon-mediated antiviral response of the host. In this proposal, the molecular mechanisms by which the NS1 protein inhibits the interferon system will be studied by comparing the phenotypic characteristics of a wild-type influenza A virus with those of a recombinant virus lacking the NS1 gene. The first aim will address the mechanism resulting in increased interferon synthesis in cells infected with the NS1 deletion virus. The second aim will examine the inhibitory effects of the NS1 protein on several key components of the type I interferon system in the absence of viral infection. In the third aim the functional contributions of the different domains of the NS1 protein on inhibition of the interferon responses will be examined. The fourth aim will assess virulence in mice using recombinant influenza viruses containing different mutations their NS1 genes. These recombinant viruses will also be characterized in mice as potential live attenuated vaccines against influenza.