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Pathogenesis of experimental skin infections induced by drug-resistant herpes simplex virus mutants
Abstract:
The comparative analysis of the pathogenicity of a parental herpes simplex virus type 1 strain and its phosphonoacetic acid (PAA)-resistant and acyclovir (ACV)-resistant mutants showed marked differences among them. After orofacial skin inoculation of hairless mice the parental and PAA-resistant viruses were detected during the first 4 days after infection at high and increasing titers in the trigeminal ganglia; the ACV-resistant mutant was present at low and decreasing titers in the ganglia. Severe and slow-healing skin lesions were produced by the parental and PAA-resistant viruses; mild and rapidly healing lesions were produced by the ACV-resistant mutant. Virus titers in ganglia and the intensity of skin lesions were related to the virus dose used in the primary infection. Latent infections became established in trigeminal ganglia of mice inoculated with 10(6.0) plaque-forming units of the parental or PAA-resistant virus; no latent infections were detected in ganglia of mice inoculated with 10(7.0) plaque-forming units of the ACV-resistant mutant. Serum antibody titers attained similar values 4 weeks after primary infection with both mutants and the parental virus. Mice infected with the ACV-resistant mutant were reinfected with the parental and PAA-resistant viruses; the degree of protection against development of skin lesions, mortality, and latency was related to the dose of ACV-resistant virus used in the primary infection. Mortality was prevented by a dose of 10(6.0) plaque-forming units, skin lesions were prevented by a dose of 10(6.5) plaque-forming units, and latency was prevented by a dose of 10(7.0) plaque-forming units of the ACV-resistant mutant. Protection against reinfection with the PAA-resistant mutant was achieved with lower doses than protection against the parental virus. Serum antibody titers showed a 4- to 15-fold increase after reinfection. The results suggest that the ACV-resistant, latency-negative mutant has many attributes of a live attenuated herpes simplex virus vaccine.
Insights
A herpes simplex virus type 1 (HSV-1) acyclovir-resistant mutant showed reduced pathogenicity and latency, offering potential as a live attenuated HSV vaccine. This mutant demonstrated protective effects against subsequent infections in mice.
Area of Science:
- Virology
- Immunology
- Vaccine Development
Background:
- Herpes simplex virus type 1 (HSV-1) causes orofacial infections and establishes latency.
- Antiviral resistance, such as to acyclovir (ACV), is a clinical concern.
- Understanding viral pathogenicity and latency is crucial for vaccine design.
Purpose of the Study:
- To compare the pathogenicity of a parental HSV-1 strain with its phosphonoacetic acid (PAA)-resistant and ACV-resistant mutants.
- To evaluate the potential of an ACV-resistant, latency-negative mutant as a live attenuated HSV vaccine.
Main Methods:
- Hairless mice were inoculated with parental HSV-1, PAA-resistant, or ACV-resistant mutant viruses.
- Viral titers in trigeminal ganglia, skin lesion severity, and latency establishment were assessed.
- Mice infected with the ACV-resistant mutant were subsequently reinoculated to assess protection.
Main Results:
- The ACV-resistant mutant exhibited significantly lower viral titers in ganglia, milder skin lesions, and failed to establish latency compared to parental and PAA-resistant viruses.
- Primary infection with the ACV-resistant mutant conferred dose-dependent protection against subsequent challenge with parental and PAA-resistant viruses.
- Serum antibody titers increased after primary infection and further upon reinfection, indicating an immune response.
Conclusions:
- The ACV-resistant, latency-negative HSV-1 mutant displays reduced pathogenicity and possesses characteristics of a live attenuated vaccine.
- This mutant demonstrates potential for inducing protective immunity against HSV-1 infection and latency.