Interferon coordinately inhibits the disruption of PML-positive ND10 and immediate-early gene expression by herpes simplex virus.
Interferons (IFNs) are important components of the innate immune response, limiting herpes simplex virus (HSV) infection. In recombinant HSV-infected cells, IFN inhibited expression of beta-galactosidase from the immediate-early gene, ICP4, promoter. The extent of inhibition was dependent on IFN dose, IFN type, cell type, and multiplicity of infection (moi). IFN inhibited gene transcription, leading to a complete block in ICP4 promoter-driven gene expression in 90% of cells. The same IFN treatments resulted in an increase in the size and number of nuclear domain 10 (ND10) structures that stained positive by immunofluorescence for the promyelocytic leukemia (PML) protein. In cultures infected at low moi with a recombinant HSV producing ICP4 as a fusion protein with green fluorescence protein, the appearance of green fluorescence in the nucleus coincided with loss of PML-positive ND10 in the same nucleus, even in the rare ICP4-expressing IFN-treated cells. IFN-dependent inhibition was nearly complete when the immediate-early promoter was in the viral genome but was minimal when the promoter was stably integrated into the cellular genome. These data reveal that IFN can completely block viral gene expression in infected cells and that enhancement of the ND10 structure, which is the site of initiation of HSV replication, correlates with the block in viral gene expression.
Taylor
J L
JL
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee 53226, USA. jtaylor@mcw.edu
Unverrich
D
D
O'Brien
W J
WJ
Wilcox
K W
KW
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002522:Chlorocebus aethiops; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D007372:Interferons / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014709:Vero Cells; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D000081:Acetamides; D017874:Immediate-Early Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C048925:herpes simplex virus, type 1 protein ICP4; C070576:PML protein, human; D007372:Interferons; D001616:beta-Galactosidase; C014026:hexamethylene bisacetamide