Viruses in the Alphavirus genus of the Togaviridae family cause significant human and animal morbidity and mortality. There is currently no specific treatment for diseases caused by these viruses. The zinc-finger antiviral protein (ZAP) is a host protein that demonstrates potent inhibition of viruses in this genus, as well as viruses in the Retroviridae and Filoviridae families. The objectives of this project are to use a genome-wide siRNA screening approach to identify host factors that are required for, or facilitate, ZAP function. We anticipate the results will help provide a comprehensive picture of the factors important for ZAP function. This information will provide the basis for interpretation of the curret information regarding ZAP's function and will stimulate new hypothesis-driven research directions. Ultimately, ideas for new approaches to treatment may be stimulated by this work, which may help prevent the devastating diseases caused by these viruses. PUBLIC HEALTH RELEVANCE: Viruses in the Alphavirus genus of the Togaviridae family cause fever, rash, arthritis, encephalitis and death. There are no specific treatments available to combat these diseases. The zinc-finger antiviral protein (ZAP) is a host protein that potently inhibits replication of the alphaviruses. The studies described in this application will screen the entire human genome for those factors that participate in ZAP's inhibitory process. Knowledge gained may lead to new treatment options.