Influenza Virus-Host Interactome Screen as a Platform for Antiviral Drug Development

Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and affect viral replication. After identifying over 1,000 host factors that coimmunoprecipitate with specific viral proteins, we generated a network of virus-host protein interactions based on the stage of the viral life cycle affected upon host factor downregulation. Using compounds that inhibit these host factors, we validated several proteins, notably Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets. Thus, virus-host interactome screens are powerful strategies to identify targetable host factors and guide antiviral drug development. [Display omitted] •Over 1,000 host proteins coprecipitate with influenza virus proteins•Knockdown of a subset of these host proteins affects influenza virus replication•The virus lifecycle involves a network of identified virus-host protein interactions•Inhibitory compounds validate several host factors as potential antiviral drug targets Host factors required for viral replication are potential drug targets. Watanabe et al. identify host factors that coimmunoprecipitate with influenza viral proteins and generate a network of virus-host protein interactions throughout the virus life cycle. Compounds inhibiting these host factors limited virus replication and thus validated these potential antiviral drug targets.