Abstract
BackgroundThe 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.ResultsWild-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.ConclusionICP0'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.
Highlights
The herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) protein is an E3 ubiquitin ligase, which is encoded within the HSV-1 latency-associated locus
Strain 129 mice, rag2-/- mice, pro-myelocytic leukemia (PML)-/ - mice, or stat1-/- mice were inoculated with 2 × 105 pfu per eye of the ICP0- virus n212 (n = 4 mice per group)
Rag2-/- stat1-/- mice and D. rag2-/- mice were inoculated with 2 × 105 pfu per eye of the ICP0- virus 0-green-fluorescent protein (GFP) or the ICP4- virus n12 (n = 4 mice per group)
Summary
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 synthesized, viral replication is efficiently initiated from virions or latent HSV-1 genomes. The regulation of gene expression from the co-linear HSV-1 and HSV-2 genomes has been described in terms of a cascade of expression of immediate-early (IE), early (E), and late (L) genes (Fig. 1A). This model was proposed 30 years ago to describe HSV-1 gene expression in cultured cells [1]. The model predicts that HSV-1 infection of a cell always leads to the production of infectious viral progeny (Fig. 1B). The model is accurate for wildtype HSV-1 in vitro, but fails to account for the most defining feature of HSV-1 and HSV-2: their capacity to establish latent infections in vivo
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