Thymidine kinase mutations conferring acyclovir resistance in herpes simplex type 1 recombinant viruses. Antimicrob Agents and Chemother

Contributions of thymidine kinase (TK) mutations to acyclovir (ACV) resistance were evaluated in herpes simplex virus type 1 recombinant viruses generated using a set of overlapping cosmids and plasmids. Alter-ations in both conserved and nonconserved regions of the TK gene were shown to confer high levels of resistance to ACV. Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) infec-tions are associated with serious complications in immunocom-promised hosts. Prolonged antiviral treatment is often re-quired for the clinical management of these patients, which could lead to the emergence of drug-resistant viruses (5, 17). Acyclovir (ACV), which has been the standard treatment for HSV infections, must be phosphorylated first by the viral thy-midine kinase (TK) and then by cellular kinases before inhib-iting the virus-encoded DNA polymerase (DNA pol) (re-viewed in reference 7). In the clinic, HSV resistance to ACV is most commonly due to mutations (substitutions, deletions, o