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.

Results from more than 15 years of H5N1 GOF studies were compiled to assist researchers at institutions worldwide in their risk assessment of naturally occurring influenza viruses to facilitate an early response in the face of emerging zoonotic influenza virus threats. Individuals or institutions tasked with risk assessment and pandemic planning must weigh the significance of the mutations detected via molecular surveillance. For example, mutations associated with some human H5N1 fatalities (e.g., PB2 627K) (39, 40) may carry more weight than those found to enhance virulence only in a mouse model (e.g., the presence of the NS1 PDZ binding domain motif) (41) . Similarly, mutations previously found to alter the receptor-binding preferences of H5N1 viruses from an ␣2,3 (avian) to ␣2,6 (human) preference would be of particular concern. Of greater concern would be the identification of mutations associated with enhanced mammalian transmissibility, including the specific amino acid residue combinations identified by Herfst et al. and Imai et al. to confer H5N1 respiratory droplet transmission in ferrets (21, 29) .