title: Multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity.
abstract: The zinc finger antiviral protein (ZAP) is a host factor that mediates inhibition of viruses in the Filoviridae, Retroviridae and Togaviridae families. We previously demonstrated that ZAP blocks replication of Sindbis virus (SINV), the prototype Alphavirus in the Togaviridae family at an early step prior to translation of the incoming genome and that synergy between ZAP and one or more interferon stimulated genes (ISGs) resulted in maximal inhibitory activity. The present study aimed to identify those ISGs that synergize with ZAP to mediate Alphavirus inhibition. Using a library of lentiviruses individually expressing more than 350 ISGs, we screened for inhibitory activity in interferon defective cells with or without ZAP overexpression. Confirmatory tests of the 23 ISGs demonstrating the largest infection reduction in combination with ZAP revealed that 16 were synergistic. Confirmatory tests of all potentially synergistic ISGs revealed 15 additional ISGs with a statistically significant synergistic effect in combination with ZAP. These 31 ISGs are candidates for further mechanistic studies. The number and diversity of the identified ZAP-synergistic ISGs lead us to speculate that ZAP may play an important role in priming the cell for optimal ISG function.
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America.
authors.forename: Sophiya
authors.initials: S
authors.lastname: Karki
authors.forename: Melody M H
authors.initials: MM
authors.lastname: Li
authors.forename: John W
authors.initials: JW
authors.lastname: Schoggins
authors.forename: Suyan
authors.initials: S
authors.lastname: Tian
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacDonald
mesh_terms: D000524:Alphavirus / Q000187:drug effects*; D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000494:pharmacology; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D051381:Rats; D012845:Sindbis Virus / Q000187:drug effects*
chemical_list: D002352:Carrier Proteins; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha; D016601:RNA-Binding Proteins; C465959:Zc3hav1 protein, rat