Characterization of herpes simplex virus type 1 thymidine kinase mutants selected under a single round of high-dose brivudin.
A broad variety of herpes simplex virus type 1 clones was selected under a single round of high-dose selection with brivudin. Mutations in the thymidine kinase (TK) genes consisted of 42% frameshift mutations within homopolymer repeats of G's and C's and single nucleotide substitutions (58%) that produced stop codons (Q261 and R281) or a new codon at the site of the substitution (A168T, R51W, G59W, G206R, R220H, Y239S, and T287 M). The A168T change, associated with an altered TK phenotype, proved to be the most commonly selected substitution. For the different mutants, a correlation between phenotype, genotype, and in vivo neurovirulence was observed.
Andrei
Graciela
G
Katholieke Universiteit Leuven, Rega Institute for Medical Research, Laboratory of Virology, Minderbroedersstraat 10, B-3000 Leuven, Belgium. graciela.andrei@rega.kuleuven.ac.be
Balzarini
Jan
J
Fiten
Pierre
P
De Clercq
Erik
E
Opdenakker
Ghislain
G
Snoeck
Robert
R
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018388:Codon, Terminator; D024882:Drug Resistance, Viral; D016368:Frameshift Mutation; D008958:Models, Molecular; D010641:Phenotype; D012641:Selection, Genetic; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics*; D013937:Thymidine Kinase / Q000737:chemistry / Q000235:genetics*; D014709:Vero Cells
D000998:Antiviral Agents; D018388:Codon, Terminator; C020235:brivudine; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine