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A thymidine kinase-negative HSV-1 strain establishes a persistent infection in SCID mice that features uncontrolled
T Valyi-Nagy1, R M Gesser, B Raengsakulrach
1Wistar Institute, Philadelphia, Pennsylvania 19104.
Abstract:
A detailed knowledge of the pathogenesis of infections caused by thymidine-kinase (TK)-deficient herpes simplex virus type 1 (HSV-1) strains is important because such mutants can arise during treatment of HSV infections with acyclovir--especially in immunocompromised patients--and also because TK-negative mutants may become useful for the therapy of intracranial tumors. In this work, we studied the pathogenesis of a genetically engineered TK-negative HSV-1 strain dlsptk, in SCID mice (mice with severe combined immunodeficiency) after corneal infection. We found that dlsptk established a persistent infection that kills SCID mice within 80.2 +/- 21.3 days. The cause of death seemed to be related to uncontrolled viral replication in the superficial and deep facial tissues of the animals. Viremia probably did not occur, as judged by the inability to detect infectious virus and viral gene expression in various internal organs. However, the virus did reach the nervous system, most probably by axonal transport from the primary site of the infection. Virus-specific DNA reached low but detectable levels in the trigeminal ganglia and the brainstems by 7 days p.i. and remained at low levels for up to 50 days p.i. as determined by spot blot analysis. By in situ hybridization and immunostaining we determined that, in some of the neurons of the trigeminal ganglia infected by the virus, viral latency was established. However, our results suggested that in other infected neurons viral replication occurred and virus spread to surrounding nonneuronal cells and to the central nervous system. This work provides a new model in which the pathogenesis of infections caused by TK-deficient HSV strains in immunocompromised hosts can be effectively studied and which may also help to identify the potential side effects of the therapy of intracranial tumors with TK-negative HSV strains.
Insights
Thymidine-kinase deficient herpes simplex virus type 1 (HSV-1) causes persistent infections and death in immunocompromised mice. This study models HSV-1 pathogenesis in SCID mice, revealing viral spread to the nervous system.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Thymidine-kinase (TK)-deficient herpes simplex virus type 1 (HSV-1) mutants are clinically relevant due to acyclovir resistance and potential use in cancer therapy.
- Understanding the pathogenesis of these TK-deficient strains is crucial for managing HSV infections and evaluating novel therapeutic strategies.
Purpose of the Study:
- To investigate the pathogenesis of a genetically engineered TK-negative HSV-1 strain (dlsptk) in severe combined immunodeficiency (SCID) mice following corneal infection.
- To establish a SCID mouse model for studying TK-deficient HSV-1 infections in immunocompromised hosts.
Main Methods:
- Corneal infection of SCID mice with the genetically engineered TK-negative HSV-1 strain dlsptk.
- Monitoring animal survival and cause of death.
- Assessing viral replication in superficial and deep facial tissues.
- Detecting infectious virus and viral gene expression in internal organs to evaluate viremia.
- Utilizing spot blot analysis, in situ hybridization, and immunostaining to detect viral DNA and gene expression in the nervous system (trigeminal ganglia, brainstem).
Main Results:
- The TK-negative HSV-1 strain dlsptk established a persistent infection, leading to mortality in SCID mice within approximately 80 days.
- Uncontrolled viral replication in facial tissues appeared to be the primary cause of death.
- Evidence suggested the virus reached the nervous system via axonal transport, with detectable viral DNA in trigeminal ganglia and brainstems.
- Both viral latency and active replication with spread to surrounding cells and the central nervous system were observed in infected neurons.
Conclusions:
- The study successfully established a SCID mouse model for investigating the pathogenesis of TK-deficient HSV-1 infections in immunocompromised individuals.
- The findings highlight the potential risks associated with TK-deficient HSV-1, including persistent infection, uncontrolled replication, and neurological dissemination.
- This model can aid in understanding potential side effects of using TK-negative HSV strains for intracranial tumor therapy.