TY - JOUR
T1 - ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus
T2 - Implications for the regulation of viral latency
AU - Halford, William P.
AU - Weisend, Carla
AU - Grace, Jennifer
AU - Soboleski, Mark
AU - Carr, Daniel J.J.
AU - Balliet, John W.
AU - Imai, Yumi
AU - Margolis, Todd P.
AU - Gebhardt, Bryan M.
PY - 2006/6/9
Y1 - 2006/6/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33748356480&partnerID=8YFLogxK
U2 - 10.1186/1743-422X-3-44
DO - 10.1186/1743-422X-3-44
M3 - Article
C2 - 16764725
AN - SCOPUS:33748356480
SN - 1743-422X
VL - 3
JO - Virology Journal
JF - Virology Journal
M1 - 44
ER -