Cooperative effects between two acyclovir resistance loci in herpes simplex virus.
The acyclovir-resistant mutant SC16 R9C2 (H.J. Field, G. Darby, and P. Wildy , J. Gen. Virol. 49:115-124, 1980) has been shown to contain two resistance loci which segregate independently on recombination with wild-type virus. One locus is in thymidine kinase, and the other is in DNA polymerase. Both induced enzymes have altered properties, thymidine kinase showing a low affinity for acyclovir and low activity, and DNA polymerase showing a low affinity for acyclovir triphosphate. Other properties of both enzymes are described which distinguish them from their wild-type counterparts. Recombinants containing either mutant thymidine kinase ( RSC -11) or mutant DNA polymerase ( RSC -26), but not both, have been used to investigate the relative contribution of each lesion to resistance and pathogenicity. Although SC16 R9C2 and both recombinants grow as well as does wild-type virus in tissue culture, they are considerably attenuated in vivo, the greatest attenuation of virulence being seen with SC16 R9C2 and RSC -26. With respect to both acyclovir resistance and in vivo growth, the lesions appear to behave synergistically. Cross resistance studies have shown the recombinant RSC -26, which contains mutant DNA polymerase but which evidently expresses wild-type thymidine kinase, to be cross resistant to both 5-iodo-2'-deoxyuridine and 5-trifluoromethyl-2'-deoxyuridine but not to (E)-5-(2-bromovinyl)-2'-deoxyuridine or 9-beta-D-arabinofuranosyladenine.
D000212:Acyclovir / Q000633:toxicity*; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D004279:DNA, Viral / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D004352:Drug Resistance, Microbial; D005260:Female; D005796:Genes / Q000187:drug effects*; D005814:Genes, Viral / Q000187:drug effects*; D007668:Kidney; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
D000998:Antiviral Agents; D004279:DNA, Viral; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D000212:Acyclovir