Effects of NS1 variants of H5N1 influenza virus on interferon induction, TNFα response and p53 activity

Non-structural protein 1 (NS1) is an important virulence factor of the highly pathogenic H5N1 avian influenza virus. A five-amino-acid (5 aa) deletion at position 80-84 and an aspartic acid to glutamic acid substitution at position 92 (D92E) are two major NS1 mutations that are highly correlated with enhanced virulence. To investigate the effect of these mutations in H5N1 virulence, three H5N1-NS1 variants were constructed: NS51 (lacking 5 aa at position 80-84), NS51(I) (carrying a 5-aa insertion at position 80-84) and NS51(IM) (carrying both the 5-aa insertion and the D92E mutation). We examined the effects of these mutations on interferon (IFN) induction, tumor-necrosis factor (TNF) a response, p53 activity and apoptosis. We found that the D92E mutation eliminated NS1's repressive effect on IFN induction, while the 5-aa deletion resulted in enhanced resistance to TNF alpha responses. We also observed that all three variants exhibited a similar suppressive effect on p53 transcriptional activity, although none of them significantly influenced apoptosis of host cells. Our findings shed new light on the role of NS1 in the pathogenicity of H5N1 virus. Cellular & Molecular Immunology (2010) 7, 235-242; doi:10.1038/cmi.2010.6; published online 15 March 2010