Open Access Research

ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency

William P Halford1*, Carla Weisend1, Jennifer Grace1, Mark Soboleski2, Daniel JJ Carr3, John W Balliet4, Yumi Imai5, Todd P Margolis5 and Bryan M Gebhardt6

Author Affiliations

1 Dept of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA

2 Dept of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA

3 Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

4 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

5 Francis I. Proctor Foundation, University of California, San Francisco, CA, USA

6 Dept of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

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Virology Journal 2006, 3:44  doi:10.1186/1743-422X-3-44

Published: 9 June 2006

Abstract

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-α/β 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-α/β receptor and the downstream transcription factor, Stat 1.

Conclusion

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.