Cell Host Microbe doi: 10.1016/j.chom.2014.11.002

Credit: ELSEVIER

Considering the limited repertoire of proteins produced by viruses as well as the high susceptibility of viral protein targets to develop drug resistance, recent antiviral drug development strategies have focused on targeting host proteins that are essential for viral replication. However, few functional analyses are available for defining relevant host-viral interactions necessary for the viral life cycle. Using interaction with host factors as a proxy for functional significance, Watanabe et al. performed a systematic biochemical analysis of interactions between viral and host proteins. Each of the 11 influenza proteins was tagged and expressed in a human cell line permissive for viral replication. Immunoprecipitation of each viral protein detected a combined 1,292 interactions with host proteins. In a secondary RNAi-based screen, the authors were able to narrow these down to 323 host genes whose decreased expression either increased or reduced viral titers. Gene ontology and pathway analyses led to a network of virus-host protein interactions with potential roles in viral replication among these hits. Among the 91 host factors with the greatest effect on viral replication upon knockdown, they identified 9 that are critical for viral genome replication and transcription, 15 involved in virion formation, 28 involved in incorporation of viral ribonucleoprotein (vRNP) complexes into progeny virions and 23 involved in early steps of the life cycle, including virus-host cell binding, internalization and transport of vRNP complexes to the nucleus. The authors next tested 11 drugs with known targets among the 299 host factors whose downregulation most inhibited viral replication, identifying several candidates that have not been proposed previously as antiviral targets, including JAK1 and a guanine nucleotide exchange factor, GBF1. This rich catalog opens new avenues to explore critical host-viral interactions at a mechanistic level and to find new antiviral targets.