Vaccinia virus K1L and C7L inhibit antiviral activities induced by type I interferons.
Cellular tropism of vaccinia virus (VACV) is regulated by host range genes, including K1L, C7L, and E3L. While E3L is known to support viral replication by antagonizing interferon (IFN) effectors, including PKR, the exact functions of K1L and C7L are unclear. Here, we show that K1L and C7L can also inhibit antiviral effectors induced by type I IFN. In human Huh7 and MCF-7 cells, a VACV mutant lacking both K1L and C7L (vK1L-C7L-) replicated as efficiently as wild-type (WT) VACV, even in the presence of IFN. However, pretreating the cells with type I IFN, while having very little effect on WT VACV, blocked the replication of vK1L-C7L- at the step of intermediate viral gene translation. Restoring either K1L or C7L to vK1L(-)C7L(-) fully restored the IFN resistance phenotype. The deletion of K1L and C7L from VACV did not affect the ability of the virus to inhibit IFN signaling or its ability to inhibit the phosphorylation of PKR and the alpha subunit of eukaryotic initiation factor 2, indicating that K1L and C7L function by antagonizing an IFN effector(s) but with a mechanism that is different from those of IFN antagonists previously identified for VACV. Mutations of K1L that inactivate the host range function also rendered K1L unable to antagonize IFN, suggesting that K1L supports VACV replication in mammalian cells by antagonizing the same antiviral factor(s) that is induced by IFN in Huh7 cells.
Meng
Xiangzhi
X
Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Jiang
Canhua
C
Arsenio
Janilyn
J
Dick
Kevin
K
Cao
Jingxin
J
Xiang
Yan
Y
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000276:immunology; D014616:Vaccinia virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D000998:Antiviral Agents; C082283:C7L protein, Vaccinia virus; D007370:Interferon Type I; C083205:K1L protein, Vaccinia virus; D014764:Viral Proteins