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

Virol J. 2006 Jun 9:3:44. doi: 10.1186/1743-422X-3-44.

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-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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Expression Regulation, Viral*
  • Herpes Simplex / immunology
  • Herpes Simplex / mortality
  • Herpes Simplex / virology*
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • L Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • STAT1 Transcription Factor / metabolism*
  • Simplexvirus / pathogenicity
  • Simplexvirus / physiology*
  • Trigeminal Ganglion / virology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Vero Cells
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Latency*

Substances

  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Rag2 protein, mouse
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Viral Proteins
  • Ubiquitin-Protein Ligases
  • Vmw110 protein, Human herpesvirus 1