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Characteristics of herpesvirus mutants resistant to phosphonoformate and phosphonoacetate
Abstract:
Mutants of herpes simplex virus type 1, resistant to phosphonoformate (PFA) and phosphonoacetate (PAA), have been selected in cell culture. The PFA-resistant mutant (HSV-PFA(r)) and the PAA-resistant mutant (HSV-PAA(r)) were also resistant to PAA and PFA, respectively. This cross-resistance indicates that PFA and PAA interact at the same site. The HSV-PFA(r) had a decreased susceptibility to vidarabine, but no difference in sensitivity to idoxuridine (5-iodo-2'-deoxyuridine) was observed when compared to the wild type. The induced deoxyribonucleic acid polymerases isolated from cells infected with HSV-PFA(r) and HSV-PAA(r) were both cross-resistant to inhibition by PFA and PAA. No increased resistance to vidarabine triphosphate could be observed, but the susceptibility to inhibition by pyrophosphate was about two times lower. None of the mutants showed any increased temperature sensitivity
Insights
Herpes simplex virus type 1 mutants resistant to phosphonoformate (PFA) and phosphonoacetate (PAA) show cross-resistance, indicating a shared interaction site. Viral DNA polymerase from these mutants is also cross-resistant to PFA and PAA.
Area of Science:
- Virology
- Molecular Biology
- Antiviral Drug Development
Background:
- Herpes simplex virus type 1 (HSV-1) is a significant human pathogen.
- Antiviral drugs like phosphonoformate (PFA) and phosphonoacetate (PAA) are used to treat HSV-1 infections.
- Understanding drug resistance mechanisms is crucial for developing effective antiviral therapies.
Purpose of the Study:
- To investigate the resistance mechanisms of HSV-1 to PFA and PAA.
- To characterize the cross-resistance patterns between PFA and PAA in HSV-1 mutants.
- To examine the properties of viral DNA polymerase in drug-resistant HSV-1 strains.
Main Methods:
- Selection of PFA-resistant (HSV-PFA(r)) and PAA-resistant (HSV-PAA(r)) HSV-1 mutants in cell culture.
- Phenotypic characterization of drug resistance in the selected mutants.
- Isolation and characterization of deoxyribonucleic acid polymerases from infected cells.
- Assessment of enzyme susceptibility to PFA, PAA, vidarabine triphosphate, and pyrophosphate.
Main Results:
- HSV-PFA(r) and HSV-PAA(r) mutants exhibited reciprocal cross-resistance to PFA and PAA, suggesting a common binding site.
- The PFA-resistant mutant showed decreased susceptibility to vidarabine but not idoxuridine.
- Viral DNA polymerases from both mutants were cross-resistant to PFA and PAA inhibition.
- Enzymes from resistant mutants had reduced susceptibility to pyrophosphate inhibition.
Conclusions:
- PFA and PAA likely target the same site in HSV-1.
- Drug resistance in HSV-1 can involve alterations in viral DNA polymerase.
- These findings provide insights into antiviral drug resistance mechanisms for HSV-1.