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Properties of a 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-resistant herpes simplex virus type 1 virus mutant
V Vonka1, E Anisimová, J Cerný
1Department of Experimental Virology, Institute of Sera and Vaccines, Prague, Czechoslovakia.
Abstract:
After repeated passages of herpes simplex type 1 (HSV-1) KOS virus in the presence of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) a mutant denoted PMEAr HSV-1 was isolated which grew well in the presence of 50-100 micrograms.ml-1 of the drug. PMEAr HSV-1 was still sensitive to the related phosphonate analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA). In fact, it was more susceptible to the action of HPMPA than the original virus. PMEAr HSV-1 also retained sensitivity to 5-bromo-2'-deoxyuridine and other, viral thymidine kinase-dependent substances such as (E)-5-(2-bromovinyl)-2'-deoxyuridine. However, PMEAr HSV-1 was much less sensitive to acyclovir, 1-(beta-D-arabinofuranosyl)cytosine and 1-(beta-D-arabinofuranosyl)thymine than the parental KOS virus.
Insights
A new herpes simplex virus type 1 (HSV-1) mutant, PMEAr HSV-1, resistant to 9-(2-phosphonylmethoxyethyl)adenine (PMEA), was developed. This mutant shows altered sensitivity to various antiviral drugs, including reduced susceptibility to acyclovir.
Area of Science:
- Virology
- Antiviral Drug Development
Background:
- Herpes simplex virus type 1 (HSV-1) is a significant human pathogen.
- Antiviral drugs like 9-(2-phosphonylmethoxyethyl)adenine (PMEA) are crucial for managing HSV-1 infections.
- Drug resistance can emerge with repeated exposure to antiviral agents.
Purpose of the Study:
- To investigate the development and characteristics of HSV-1 resistance to PMEA.
- To evaluate the cross-resistance and sensitivity profiles of PMEA-resistant HSV-1 (PMEAr HSV-1) to other antiviral compounds.
Main Methods:
- Serial passage of HSV-1 KOS strain in the presence of increasing concentrations of PMEA.
- Isolation and characterization of the PMEA-resistant mutant (PMEAr HSV-1).
- Antiviral susceptibility testing of PMEAr HSV-1 against PMEA, HPMPA, and other nucleoside analogues.
Main Results:
- A PMEA-resistant HSV-1 mutant (PMEAr HSV-1) was successfully isolated, exhibiting robust growth in the presence of 50-100 µg/mL PMEA.
- PMEAr HSV-1 remained sensitive to (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), showing even increased susceptibility compared to the parental virus.
- The mutant retained sensitivity to thymidine kinase-dependent drugs like 5-bromo-2'-deoxyuridine and (E)-5-(2-bromovinyl)-2'-deoxyuridine.
- PMEAr HSV-1 displayed significantly reduced sensitivity to acyclovir, 1-(beta-D-arabinofuranosyl)cytosine, and 1-(beta-D-arabinofuranosyl)thymine compared to the wild-type KOS virus.
Conclusions:
- Repeated exposure to PMEA can induce resistance in HSV-1.
- PMEAr HSV-1 exhibits a distinct resistance profile, with cross-resistance to some drugs and hypersensitivity to others.
- Understanding these resistance mechanisms is vital for developing effective antiviral strategies against HSV-1.