ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency.
BACKGROUND
The herpes simplex virus type 1 (HSV-1) ICP0 protein is an E3 ubiquitin ligase, which is encoded within the HSV-1 latency-associated locus. When ICP0 is not synthesized, the HSV-1 genome is acutely susceptible to cellular repression. Reciprocally, when ICP0 is synthesized, viral replication is efficiently initiated from virions or latent HSV-1 genomes. The current study was initiated to determine if ICP0's putative role as a viral interferon (IFN) antagonist may be relevant to the process by which ICP0 influences the balance between productive replication versus cellular repression of HSV-1.


RESULTS
Wild-type (ICP0+) strains of HSV-1 produced lethal infections in scid or rag2-/- mice. The replication of ICP0- null viruses was rapidly repressed by the innate host response of scid or rag2-/- mice, and the infected animals remained healthy for months. In contrast, rag2-/- mice that lacked the IFN-alpha/beta receptor (rag2-/- ifnar-/-) or Stat 1 (rag2-/- stat1-/-) failed to repress ICP0- viral replication, resulting in uncontrolled viral spread and death. Thus, the replication of ICP0- viruses is potently repressed in vivo by an innate immune response that is dependent on the IFN-alpha/beta receptor and the downstream transcription factor, Stat 1.


CONCLUSIONS
ICP0's function as a viral IFN antagonist is necessary in vivo to prevent an innate, Stat 1-dependent host response from rapidly repressing productive HSV-1 replication. This antagonistic relationship between ICP0 and the host IFN response may be relevant in regulating whether the HSV-1 genome is expressed, or silenced, in virus-infected cells in vivo. These results may also be clinically relevant. IFN-sensitive ICP0- viruses are avirulent, establish long-term latent infections, and induce an adaptive immune response that is highly protective against lethal challenge with HSV-1. Therefore, ICP0- viruses appear to possess the desired safety and efficacy profile of a live vaccine against herpetic disease.
Halford
William P
WP
Dept of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA. halford@montana.edu
Weisend
Carla
C
Grace
Jennifer
J
Soboleski
Mark
M
Carr
Daniel J J
DJ
Balliet
John W
JW
Imai
Yumi
Y
Margolis
Todd P
TP
Gebhardt
Bryan M
BM
D000818:Animals; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D015967:Gene Expression Regulation, Viral; D006561:Herpes Simplex / Q000276:immunology / Q000401:mortality / Q000821:virology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007739:L Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D018139:Simplexvirus / Q000472:pathogenicity / Q000502:physiology*; D012668:Trigeminal Ganglion / Q000821:virology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C499308:Rag2 protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1