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Phenotypic and genotypic characterization of clinical isolates of herpes simplex virus resistant to aciclovir

GlaxoSmithKline, UK Virology Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK

Correspondence
Rob Fenton
rob.j.fenton{at}gsk.com

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.