Pathogenic Influenza Viruses and Coronaviruses Utilize Similar and Contrasting Approaches To Control Interferon-Stimulated Gene Responses

Menachery, Vineet D.; Eisfeld, Amie J.; Schäfer, Alexandra; Josset, Laurence; Sims, Amy C.; Proll, Sean; Fan, Shufang; Li, Chengjun; Neumann, Gabriele; Tilton, Susan C.; Chang, Jean; Gralinski, Lisa E.; Long, Casey; Green, Richard; Williams, Christopher M.; Weiss, Jeffrey; Matzke, Melissa M.; Webb-Robertson, Bobbie-Jo; Schepmoes, Athena A.; Shukla, Anil K.; Metz, Thomas O.; Smith, Richard D.; Waters, Katrina M.; Katze, Michael G.; Kawaoka, Yoshihiro; Baric, Ralph S.

While NS1 histone mimicry has been identified in an H3N2 virus, the responsible binding motif is not contained in either H5N1-VN1203 or 1918 H1N1 (24) . This suggests that the C-terminal portion of NS1 may mediate selective ISG subset downregulations through different mechanisms depending on strain. For H5N1-VN1203, NS1 may target a similar functional pathway as H3N2 by mimicking different histones, targeting histone-modifying enzymes, or disrupting a histone adaptor protein complex. For H1N1-09, it suggests that the absent 11-aminoacid C-terminal truncation of NS1 may contribute to its relative lack of ISG antagonism; this absent tail has multiple functional domains in addition to possible histone modification elements (17, 46, 47) . Together, these possibilities illustrate the complexity of NS1 and the caveats of analyzing its contribution to histone modification; however, further study with the plethora of H5N1-VN1203 and H1N1-09 viral mutants provides a golden opportunity to further characterize NS1's role in ISG manipulation.