Herpes simplex virus resistance and sensitivity to phosphonoacetic acid

Area of Science:

• Virology
• Molecular Biology
• Antiviral Drug Development

Background:

• Phosphonoacetic acid (PAA) is known to inhibit herpes simplex virus (HSV) replication.
• Understanding the precise mechanism of PAA action and the genetic basis of resistance is crucial for antiviral therapy.

Purpose of the Study:

• To investigate the effect of PAA on HSV DNA synthesis and protein production.
• To characterize PAA-resistant HSV mutants and their genetic properties.
• To confirm the role of HSV DNA polymerase as the target of PAA.

Main Methods:

• Inhibition assays of HSV DNA synthesis and DNA polymerase activity in vitro.
• Analysis of viral protein synthesis in PAA-treated and untreated infected cells.
• Selection and isolation of PAA-resistant HSV mutants.
• Complementation and recombination studies with PAA-resistant and sensitive HSV strains.

Main Results:

• PAA effectively inhibited HSV DNA synthesis and late viral protein production, while early protein synthesis remained largely unaffected.
• Sequential selection yielded HSV mutants with increasing resistance to PAA, correlated with resistance in DNA synthesis and polymerase activity.
• PAA-resistant HSV-1 strains demonstrated complementation of sensitive strains in mixed infections.
• Recombination studies indicated high-frequency linkage of the PAA resistance marker to the HSV DNA polymerase gene.

Conclusions:

• The herpesvirus DNA polymerase is confirmed as the primary target of phosphonoacetic acid.
• PAA-resistant HSV mutants are valuable tools for genetic analysis of herpesviruses.
• These findings support the development of PAA-based antiviral strategies and resistance management.