Slipping and sliding: Frameshift mutations in herpes simplex virus thymidine kinase and drug-resistance

► Although acyclovir and related compounds are effective herpes simplex virus therapies, drug resistance is an important clinical problem. ► Frameshift mutations in the viral thymidine kinase gene, which encodes the enzyme that activates acyclovir, are frequently observed in drug-resistant viruses. ► The frameshift mutations may be associated with low levels of thymidine kinase expression; too low to activate drug but sufficient to support pathogenesis. ► Mechanisms exploited to compensate for frameshift mutations include ribosomal frameshifting, internal ribosome entry, and induced infidelity of the DNA polymerase.