Herpes simplex virus-1 infection causes the secretion of a type I interferon-antagonizing protein and inhibits signaling at or before Jak-1 activation.
Host cells respond to viral infection by the production of type I interferons (IFNs), which induce the expression of antiviral genes. Herpes simplex virus I (HSV-1) encodes many mechanisms that inhibit the type I IFN response, including the ICP27-dependent inhibition of type I IFN signaling. Here we show inhibition of Stat-1 nuclear accumulation in cells that express ICP27. ICP27 expression also induces the secretion of a small, heat-stable type I IFN antagonizing protein that inhibits Stat-1 nuclear accumulation. We show that the inhibition of IFN-induced Stat-1 phosphorylation occurs at or upstream of Jak-1 phosphorylation. Finally, we show that ISG15 expression is induced after IFNalpha treatment in mock-infected cells, but not cells infected with WT HSV-1 or ICP27(-) HSV-1. These data suggest that HSV-1 has evolved multiple mechanisms to inhibit IFN signaling not only in infected cells, but also in neighboring cells, thereby allowing for increased viral replication and spread.
Johnson
Karen E
KE
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.
Knipe
David M
DM
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000235:genetics; D005455:Fluorescent Antibody Technique; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D017874:Immediate-Early Proteins / Q000502:physiology; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D053613:Janus Kinase 1 / Q000502:physiology; D010766:Phosphorylation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000032:analysis / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014452:Ubiquitins / Q000235:genetics; D014709:Vero Cells
D016207:Cytokines; C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D007370:Interferon Type I; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D014452:Ubiquitins; D053633:Receptor, Interferon alpha-beta; C074034:ISG15 protein, human; D053613:Janus Kinase 1