ICP0 antagonizes Stat I-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 ( ICPO+) strains of HSV-1 produced lethal infections in scid or rag(2-/-) mice. The replication of ICP0(-) null viruses was rapidly repressed by the innate host response of scid or rag(2-/-) mice, and the infected animals remained healthy for months. In contrast, rag(2-/-) mice that lacked the IFN-alpha/beta receptor (rag(2-/-) ifnar(-/-)) or Stat 1 (rag2-/- stat 1(-/-)) 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 I-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. Background Herpesviruses are double-stranded DNA viruses that establish life-long infections in their animal hosts, and which alternate between two programs of gene expression: i. productive replication, or ii. latent infection in which most of the viral genome is transcriptionally silent.