title: C7L family of poxvirus host range genes inhibits antiviral activities induced by type I interferons and interferon regulatory factor 1.
abstract: Vaccinia virus (VACV) K1L and C7L function equivalently in many mammalian cells to support VACV replication and antagonize antiviral activities induced by type I interferons (IFNs). While K1L is limited to orthopoxviruses, genes that are homologous to C7L are found in diverse mammalian poxviruses. In this study, we showed that the C7L homologues from sheeppox virus and swinepox virus could rescue the replication defect of a VACV mutant deleted of both K1L and C7L (vK1L(-)C7L(-)). Interestingly, the sheeppox virus C7L homologue could rescue the replication of vK1L(-)C7L(-) in human HeLa cells but not in murine 3T3 and LA-4 cells, in contrast to all other C7L homologues. Replacing amino acids 134 and 135 of the sheeppox virus C7L homologue, however, made it functional in the two murine cell lines, suggesting that these two residues are critical for antagonizing a putative host restriction factor which has some subtle sequence variation in human and murine cells. Furthermore, the C7L family of host range genes from diverse mammalian poxviruses were all capable of antagonizing type I IFN-induced antiviral activities against VACV. Screening of a library of more than 350 IFN-stimulated genes (ISGs) identified interferon-regulated factor 1 (IRF1) as an inhibitor of vK1L(-)C7L(-) but not wild-type VACV. Expression of either K1L or C7L, however, rendered vK1L(-)C7L(-) resistant to IRF1-induced antiviral activities. Altogether, our data show that K1L and C7L antagonize IRF1-induced antiviral activities and that the host modulation function of C7L is evolutionally conserved in all poxviruses that can readily replicate in tissue-cultured mammalian cells.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.forename: John
authors.initials: J
authors.lastname: Schoggins
authors.forename: Lloyd
authors.initials: L
authors.lastname: Rose
authors.forename: Jingxin
authors.initials: J
authors.lastname: Cao
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018151:Capripoxvirus / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D023061:Gene Order; D058507:Host Specificity / Q000235:genetics*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011212:Poxviridae / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D018148:Suipoxvirus / Q000235:genetics / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics
chemical_list: C082283:C7L protein, Vaccinia virus; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; C083205:K1L protein, Vaccinia virus; D014764:Viral Proteins