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Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes
D A Leib1, D M Coen, C L Bogard
1Laboratory of Tumor Virus Genetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Using nonsense and deletion mutants of herpes simplex virus type 1, we investigated the roles of three immediate-early proteins (ICP4, ICP27 and ICP0) in the establishment and reactivation of ganglionic latency in a mouse ocular model. DNA hybridization, superinfection-rescue, and cocultivation techniques provided quantitative data that distinguished between the failure of a virus to establish latency in the ganglion and its failure to reactivate. Null mutants with lesions in the genes for ICP4 and ICP27 did not replicate in the eye or in ganglia and failed to establish reactivatable latent infections. Three ICP0 deletion mutants which could replicate in the eye and ganglia varied in their ability to establish and reactivate from the latent state, demonstrating that ICP0 plays a role both in the establishment and the reactivation of latency. The use of viral mutants and a variety of stage-specific assays allowed us to better define the stages in the establishment and reactivation of herpes simplex virus type 1 latency.
Insights
Herpes simplex virus type 1 immediate-early proteins ICP4 and ICP27 are essential for establishing latent infections. ICP0 is crucial for both establishing and reactivating latency from ganglia.
Area of Science:
- Virology
- Immunology
- Ophthalmology
Background:
- Herpes simplex virus type 1 (HSV-1) establishes lifelong latent infections in sensory ganglia.
- Understanding the viral factors governing latency is crucial for developing antiviral strategies.
Purpose of the Study:
- To elucidate the roles of HSV-1 immediate-early proteins ICP4, ICP27, and ICP0 in the establishment and reactivation of ganglionic latency.
- To differentiate between failures in latency establishment and reactivation using specific viral mutants.
Main Methods:
- Utilized nonsense and deletion mutants of HSV-1.
- Employed DNA hybridization, superinfection-rescue, and cocultivation assays for quantitative analysis.
- Investigated latency in a mouse ocular model.
Main Results:
- ICP4 and ICP27 null mutants failed to replicate and establish latent infections.
- ICP0 deletion mutants showed variable abilities in establishing and reactivating latency, indicating a dual role.
- Distinguished between latency establishment and reactivation failures.
Conclusions:
- ICP4 and ICP27 are indispensable for HSV-1 latency establishment.
- ICP0 plays a significant role in both the establishment and reactivation phases of HSV-1 latency.
- This study provides a refined understanding of HSV-1 latency dynamics.