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The role of herpesvirus type 1 thymidine kinase in experimental ocular infections
Abstract:
Herpesvirus type 1 thymidine-kinase-negative mutants are readily selected for in tissue culture and in humans by acyclovir, a promising antiviral agent. We investigated the ocular pathogenicity of thymidine-kinase-negative mutants in the rabbit. The natural course of untreated keratitis induced by the herpesvirus type 1 thymidine-kinase-negative strain was characterized by superficial dendrites and geographic ulcers that healed spontaneously without loss of corneal clarity. We also studied the relationship between herpesvirus type 1 thymidine-kinase activity and virulence in the rabbit with three strains of herpesvirus type 1: NIH thymidine-kinase-positive (100% thymidine-kinase activity), NIH thymidine-kinase-intermediate (25% thymidine-kinase activity), and NIH thymidine-kinase-negative (0% thymidine-kinase activity). Despite comparable ocular titers, the NIH thymidine-kinase-positive strain proved to be the most virulent, causing significantly (P less than .002) more keratitis, encephalitis, and death than the other strains.
Insights
Herpes simplex virus type 1 thymidine kinase-negative mutants cause mild ocular disease. However, thymidine kinase-positive strains are more virulent, leading to severe keratitis, encephalitis, and death in rabbits.
Area of Science:
- Virology
- Ophthalmology
- Immunology
Background:
- Herpes simplex virus type 1 (HSV-1) thymidine kinase-negative mutants are selected by acyclovir, an antiviral drug.
- Understanding the pathogenicity of these mutants is crucial for antiviral therapy development.
Purpose of the Study:
- To investigate the ocular pathogenicity of HSV-1 thymidine kinase-negative mutants in a rabbit model.
- To determine the relationship between HSV-1 thymidine kinase activity and viral virulence.
Main Methods:
- Induction of keratitis in rabbits using HSV-1 thymidine kinase-negative strains.
- Comparison of ocular pathogenicity and virulence among HSV-1 strains with varying thymidine kinase activity (positive, intermediate, negative).
- Monitoring of clinical signs, viral titers, and outcomes including keratitis, encephalitis, and mortality.
Main Results:
- HSV-1 thymidine kinase-negative strains induced superficial keratitis that healed spontaneously without corneal opacity.
- Despite similar ocular viral loads, the thymidine kinase-positive HSV-1 strain exhibited significantly higher virulence.
- The thymidine kinase-positive strain caused more severe keratitis, encephalitis, and mortality compared to intermediate and negative strains (P < .002).
Conclusions:
- HSV-1 thymidine kinase-negative mutants demonstrate reduced ocular pathogenicity in rabbits.
- HSV-1 thymidine kinase activity is directly correlated with viral virulence, impacting disease severity and outcome.
- These findings have implications for understanding HSV-1 pathogenesis and the efficacy of acyclovir in treating HSV-1 infections.