Use of Highly Pathogenic Avian Influenza A(H5N1) Gain-Of-Function Studies for Molecular-Based Surveillance and Pandemic Preparedness

Davis, C. Todd; Chen, Li-Mei; Pappas, Claudia; Stevens, James; Tumpey, Terrence M.; Gubareva, Larisa V.; Katz, Jacqueline M.; Villanueva, Julie M.; Donis, Ruben O.; Cox, Nancy J.

The recent emergence of low-pathogenicity avian influenza (LPAI) H7N9 virus causing human infections in China, like the emergence of pandemic influenza A(H1N1) virus in 2009, was instructive from a molecular surveillance perspective because the HA and neuraminidase (NA) genes were not closely related to those of previously recognized influenza A viruses (48) . Despite the lack of high sequence identity of this H7N9 virus to other known viruses, many structural and functional motifs between this LPAI H7N9 and HPAI H5N1 viruses remain conserved, particularly the amino acid domains making up the three major structural elements of the receptor binding site (RBS) (49) . In addition, NA enzymatic active sites, which are targets of NA inhibitors, share homology with NA proteins from H5N1 and other influenza A subtype viruses (48) . Finally, the internal genes described for H7N9 viruses share common ancestry with H9N2 lineage viruses, ancestry that is retained in the internal genes of many H5N1 genotypes. Thus, many of the GOF mutations described for both surface and internal protein sequences of H5N1 viruses were assessed in the context of H7N9 virus sequences as they were deposited in databases during the early wave of human infections in China.