In mice, influenza virus resistance is strongly dependent on the interferon (IFN)-regulated Mx1 gene which encodes a potent restriction factor that inhibits a poorly defined early step of the viral life cycle. Humans possess two IFN-regulated Mx genes with antiviral activity. The human Mx1 gene (encoding MxA protein) confers resistance to a broad range of RNA viruses in cell culture, including influenza A viruses, whereas the human Mx2 gene (encoding MxB protein) has been shown to inhibit HIV-1.
To determine whether human MxA plays a decisive role in defending the intact organism against influenza A viruses, we developed a mouse strain that lacks functional endogenous Mx genes but carries the complete human Mx locus as a transgene. MxA-transgenic mice exhibited solid resistance to infection with highly pathogenic H5N1 and H7N7 avian influenza viruses, as well as influenza-like Thogoto virus. However, transgenic mice differed only slightly from non-transgenic littermates with regard to resistance to H1N1 and H3N2 influenza viruses of human origin, suggesting that seasonal human influenza viruses have acquired adaptive mutations which permit MxA evasion.
To identify adaptive mutations which confer Mx resistance, we passaged mouse-adapted H7N7 avian influenza virus SC35M in MxA-transgenic mice. Here we will describe an escape variant of SC35M resulting from this screen that induces fatal disease in MxA-transgenic mice and exhibits enhanced virulence for mice with intact endogenous Mx1 genes.