Acyclovir is phosphorylated to its active form by a viral enzyme. Which enzyme is responsible for the first phosphorylation step in HSV-infected cells?

Explanation

## Acyclovir Activation and Selectivity ### Mechanism of Viral Phosphorylation Acyclovir is a prodrug that requires sequential phosphorylation to become active: 1. **First phosphorylation (monophosphate):** Viral thymidine kinase (TK) 2. **Second phosphorylation (diphosphate):** Host cell guanylate kinase 3. **Third phosphorylation (triphosphate):** Host cell nucleotide kinases Only the triphosphate form is the active inhibitor of viral DNA polymerase. **Key Point:** Viral thymidine kinase is essential for the initial activation step. This enzyme is produced only by herpesviruses (HSV-1, HSV-2, VZV), which explains acyclovir's selectivity for these viruses. ### Basis of Selectivity ```mermaid flowchart TD A[Acyclovir enters cell]:::outcome --> B{Viral TK present?}:::decision B -->|Yes| C[Monophosphate formed]:::action C --> D[Host kinases: diphosphate]:::action D --> E[Host kinases: triphosphate]:::action E --> F[Inhibits viral DNA polymerase]:::action F --> G[Viral DNA synthesis blocked]:::outcome B -->|No| H[Acyclovir inactive]:::outcome ``` ### Clinical Implications **High-Yield:** Acyclovir resistance can develop through two mechanisms: - **TK-deficient mutants:** Lack viral thymidine kinase → cannot phosphorylate acyclovir - **DNA polymerase mutants:** Altered viral DNA polymerase that does not recognize acyclovir-TP **Clinical Pearl:** TK-deficient HSV mutants are resistant to acyclovir but remain sensitive to foscarnet (which does not require viral TK activation). ### Comparison of Herpesvirus Antivirals | Drug | Activation | Spectrum | Resistance | |------|------------|----------|------------| | Acyclovir | Viral TK | HSV-1, HSV-2, VZV | TK-deficient mutants | | Valacyclovir | Viral TK (prodrug) | HSV-1, HSV-2, VZV | TK-deficient mutants | | Ganciclovir | Viral protein kinase | CMV, HSV, VZV | Less common than acyclovir | | Foscarnet | None (pyrophosphate) | CMV, HSV, VZV, resistant strains | Rare; used for resistant cases | **Warning:** Do not confuse viral thymidine kinase with host cell thymidine kinase. Host TK cannot phosphorylate acyclovir efficiently, which is why acyclovir is selective for virus-infected cells.