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

Some of the most successful antiviral agents currently available are effective against herpes simplex virus. However, resistance to these drugs is frequently associated with significant morbidity, particularly in immunocompromised patients. In addition to the clinical implications of drug resistance, the range of biological processes exploited by the virus to attain resistance while maintaining pathogenicity is proving to be surprising. These mechanisms, which include ribosomal frameshifting, induced infidelity of the DNA polymerase, and internal ribosome entry, are discussed.

► 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.