Min_Nat_Biotechnol_2010 - NEWS AND VIEWS Cellular targets...

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NATURE BIOTECHNOLOGY VOLUME 28 NUMBER 3 MARCH 2010 239 regulated susceptibility or resistance to influenza PR8 virus infection. Notably, they demonstrated that interferon-inducible transmembrane proteins inhibit an early step of influenza replication. König et al. 3 infected siRNA-transfected cells with a recombinant influenza A/WSN/33 (WSN) virus in which the coding region of hemagglu- tinin was replaced by a luciferase reporter gene. The absence of functional hemagglutinin pro- tein in this screen limited it to identifying genes involved in early stages of infection (viral entry, uncoating and nuclear import), as well as viral RNA transcription and translation. Late events, such as virus assembly, budding and release, could not be scored. These authors found 295 the host cell, virus entry through endocytosis, fusion of the endosomal and viral membranes to allow uncoating of the virus particle, and transport of the viral components to the nucleus, where transcription and replication take place. The late events include export of the viral ribonucleoprotein complex and RNA into the cytoplasm, where translation and viral assembly occur, and release of prog- eny virions from the cell surface. Brass et al. 1 used fluorescence microscopy to score the abundance of the influenza enve- lope glycoprotein hemagglutinin as a marker of infection with influenza A/PR/8/34 (PR8) virus in siRNA-treated osteosarcoma cells and identified 312 human genes that Seasonal influenza causes hundreds of thousands of deaths annually, and the potential for vastly higher mortality from an influenza pandemic remains an ever-present threat to global health. Two recent papers in Cell 1,2 and two in Nature 3,4 describe a significant advance in the search for new influenza drugs. The studies reveal hun- dreds of human genes that are required for the influenza replicative cycle, at least some of which may emerge as novel drug targets. Like almost all mammalian viruses, influenza virus has evolved strategies for exploiting host cell factors to promote its replication and sup- press antiviral immune responses. Identification of these host factors would expand the number of potential drug targets far beyond the 11 pro- teins encoded in the viral genome. To discover and validate human genes implicated in the influenza life cycle, all four research teams 1–4 transfected cultured human cells with pools of short interfering (si)RNAs designed to silence the majority of human genes and monitored the effects of knocking down individual genes on viral infectivity. Initial hits from each study were used to search databases of protein-pro- tein interactions, allowing prediction of host- cell pathways that are likely to be needed either for the viral replicative cycle or for the immune response to viral infection. High-throughput siRNA screens of human
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Min_Nat_Biotechnol_2010 - NEWS AND VIEWS Cellular targets...

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