A patient develops widespread vesicles on erythematous skin in a dermatomal distribution on the trunk. He is started on acyclovir. What is the mechanism by which varicella-zoster virus (VZV) develops resistance to acyclovir?

• A Mutation in viral DNA polymerase reducing acyclovir triphosphate binding
• B Mutation in viral thymidine kinase (TK) reducing phosphorylation of acyclovir to acyclovir monophosphate ✓
• C Upregulation of viral efflux pumps preventing intracellular acyclovir accumulation
• D Increased viral ribonucleotide reductase bypassing TK-dependent activation

Explanation

Acyclovir resistance in herpesviruses (HSV and VZV) most commonly occurs through mutations in viral thymidine kinase (TK), the enzyme that phosphorylates acyclovir to its monophosphate form (the first and rate-limiting step). Without TK activity, acyclovir cannot be activated. DNA polymerase mutations are a less common mechanism. For TK-mutant acyclovir-resistant herpesvirus infections, foscarnet (does not require TK activation) or cidofovir are used as alternatives.

Reference: Neena Khanna Illustrated Synopsis of Dermatology & STD, 6th ed.

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Written and medically reviewed by the StethoPrep medical team.