Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites.
Earlier studies have shown that herpes simplex virus 1 (HSV-1) blocks the interferon response pathways, at least at two sites, by circumventing the effects of activation of protein kinase R by double-stranded RNA and interferon and through the degradation of promyelocytic leukemia protein (PML) since interferon has no antiviral effects in PML(-/-) cells. Here we report on two effects of viral genes on other sites of the interferon signaling pathway. (i) In infected cells, Jak1 kinase associated with interferon receptors and Stat2 associated with the interferon signaling pathway rapidly disappear from infected cells. The level of interferon alpha receptor is also reduced, albeit less drastically at times after 4 h postinfection. Other members of the Stat family of proteins were either decreased in amount or posttranslationally processed in a manner different from those of mock-infected cells. The decrease in the levels of Jak1 and Stat2 may account for the decrease in the formation of complexes consisting of Stat1 or ISGF3 and DNA sequences containing the interferon-stimulated response elements after exposure to interferon. (ii) The disappearance of Jak1 and Stat2 was related at least in part to the function of the virion host shutoff protein, the product of the viral U(L)41 gene. Consistent with this observation, a mutant lacking the U(L)41 gene and treated with interferon produced lesser amounts of a late protein (U(L)38) than the wild-type parent. We conclude that HSV-1 blocks the interferon signaling pathways at several sites.
Chee
Ana Virginia
AV
The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois 60637, USA.
Roizman
Bernard
B
D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000502:physiology*; D053613:Janus Kinase 1; D008954:Models, Biological; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
D036022:Capsid Proteins; D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C081688:Ul41 protein, Human herpesvirus 1; C082563:VP19 protein, Human herpesvirus 1; D014764:Viral Proteins; D007371:Interferon-gamma; D007372:Interferons; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D019892:eIF-2 Kinase