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

William P. Halford, Carla Weisend, Jennifer Grace, Mark Soboleski, Daniel J.J. Carr, John W. Balliet, Yumi Imai, Todd P. Margolis, Bryan M. Gebhardt

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish
Article number44
JournalVirology Journal
Volume3
DOIs
StatePublished - Jun 9 2006

Fingerprint

Dive into the research topics of 'ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: Implications for the regulation of viral latency'. Together they form a unique fingerprint.

Cite this