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Induction of acyclovir-resistant mutants of herpes simplex virus type I in athymic nude mice
Abstract:
Induction of acyclovir resistance was studied in the immune compromised host by multiple passage of plaque-purified herpes simplex type I strains in athymic nude mice receiving suboptimal antiviral therapy. Mice infected with a highly pathogenic clinical isolate rapidly developed infections that were resistant to therapy. Viruses isolated from these mice had decreased in-vitro sensitivities to acyclovir, as well as altered characteristics when assayed by [125I]plaque autoradiography. In contrast, less virulent laboratory strains, or a genetically stable clinical isolate, showed no indication of mutation to resistance after extended passage in this mouse model. Highly pathogenic viruses may increase the probability of mutation to resistance because of the large amount of infectious virus they produce, while viruses of equivalent virulence may produce different amounts of drug-resistant progeny because of alterations in the replication fidelity of the viral DNA polymerase.
Insights
Highly pathogenic herpes simplex virus (HSV) strains rapidly develop acyclovir resistance in immunocompromised mice. Viral factors, like DNA polymerase fidelity, influence drug resistance development.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Acyclovir is a primary antiviral medication for herpes simplex virus (HSV) infections.
- Understanding the mechanisms of antiviral resistance is crucial for effective treatment strategies.
- Immune compromised hosts are particularly vulnerable to persistent and drug-resistant viral infections.
Purpose of the Study:
- To investigate the induction of acyclovir resistance in herpes simplex type I strains within an immunocompromised host model.
- To determine the influence of viral pathogenicity and replication fidelity on the development of drug resistance.
Main Methods:
- Multiple passage of plaque-purified HSV-1 strains in athymic nude mice under suboptimal acyclovir therapy.
- Assessing in-vitro acyclovir sensitivity of isolated viruses.
- Characterizing viral alterations using [125I]plaque autoradiography.
Main Results:
- Highly pathogenic HSV-1 clinical isolates rapidly acquired acyclovir resistance in vivo.
- Resistant viruses exhibited decreased in-vitro acyclovir sensitivity and altered characteristics.
- Less virulent laboratory strains or genetically stable clinical isolates did not develop resistance under similar conditions.
Conclusions:
- Viral pathogenicity and the quantity of infectious virus produced are key factors in the rapid development of acyclovir resistance.
- Alterations in viral DNA polymerase replication fidelity may explain differential drug-resistant progeny production among viruses of equivalent virulence.