Phenotypic and genotypic characterization of clinical isolates of herpes simplex virus resistant to aciclovir.
A panel of 10 clinical isolates of herpes simplex virus (HSV) deficient in the expression of thymidine kinase (TK) and phenotypically resistant to aciclovir was characterized. Sequence analysis revealed a variety of mutations in TK (nucleotide substitutions, insertions and deletions), most of which resulted in truncated TK polypeptides. In line with previous reports, the most common mutation was a single G insertion in the 'G-string' motif. One HSV-1 isolate and two HSV-2 isolates appeared to encode full-length polypeptides and, in each case, an amino acid substitution likely to be responsible for the phenotype was identified. Pathogenicity was determined using a zosteriform model of HSV infection in BALB/c mice. The majority of isolates appeared to show impaired growth at the inoculation site compared with wild-type virus. They also showed poor replication in the peripheral nervous system and little evidence of zosteriform spread. One exception was isolate 4, which had a double G insertion in the G-string but, nevertheless, exhibited zosteriform spread. These studies confirmed that TK-deficient viruses display a range of neurovirulence with respect to latency and zosteriform spread. These results are discussed in the light of previous experience with TK-deficient viruses.
Harris
Wendy
W
GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Collins
Peter
P
GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Fenton
Rob J
RJ
GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Snowden
Wendy
W
GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Sowa
Mike
M
GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Darby
Graham
G
GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D005814:Genes, Viral; D005838:Genotype; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010641:Phenotype; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification*; D013937:Thymidine Kinase / Q000235:genetics; D014709:Vero Cells; D014774:Virulence / Q000235:genetics
D000998:Antiviral Agents; D004279:DNA, Viral; D013937:Thymidine Kinase; D000212:Acyclovir