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.

However, examination of influenza sequence data alone does not allow us to assess the pandemic potential of a virus. Pandemic risk assessment that utilizes sequence data can take place only after critical genetic signatures are identified through laboratory research into the consequences for relevant biological properties (or phenotypes). These critical genetic features include those that based on previous experimental validation are predicted to confer virulence and/or have the ability to transmit efficiently in mammals. In this context, genomes are sequenced, mutations are detected relative to earlier viruses and prototype strains, significance is appraised based on prior knowledge of genetic markers, and phenotypes are tested using a variety of in vitro and in vivo experiments. Viruses possessing phenotypes of interest or concern often become candidates for reverse-genetics studies, which are essential to elucidate the precise molecular correlate(s) of a given phenotype (Fig. 1) . From a molecular epidemiological perspective, this process is at the heart of how the public health community makes informed decisions about the threat posed by zoonotic influenza viruses and which interventions might be most effective (7) .