Which viral protein is the primary target of acyclovir in the treatment of herpes simplex virus infection?

Explanation

## Mechanism of Acyclovir Action **Key Point:** Acyclovir is a nucleoside analogue that selectively inhibits viral DNA polymerase, not the viral enzyme that phosphorylates it. ### Why Viral DNA Polymerase? Acyclovir undergoes a three-step phosphorylation process: 1. Viral thymidine kinase (TK) phosphorylates acyclovir to acyclovir monophosphate 2. Cellular enzymes convert it to acyclovir triphosphate 3. Acyclovir triphosphate competitively inhibits **viral DNA polymerase** and causes chain termination **High-Yield:** The selectivity of acyclovir for HSV-infected cells depends on: - High levels of viral thymidine kinase in infected cells - Viral DNA polymerase has 40–200 times higher affinity for acyclovir triphosphate than cellular DNA polymerase - This explains why acyclovir has minimal toxicity to uninfected host cells ### Viral Thymidine Kinase — Not the Direct Target While viral TK is essential for acyclovir activation, it is not the target of inhibition. TK-deficient HSV mutants are resistant to acyclovir because the drug cannot be phosphorylated, not because TK itself is blocked. **Clinical Pearl:** Acyclovir-resistant HSV strains typically have mutations in viral TK (most common) or viral DNA polymerase (less common), confirming that DNA polymerase is the final therapeutic target. [cite:Harrison 21e Ch 187]