Construction of a herpes simplex virus/varicella-zoster virus (HSV/VZV) thymidine kinase recombinant with the pathogenic potential of HSV and a drug sensitivity profile resembling that of VZV.
A recombinant of herpes simplex virus (HSV) was constructed in which the HSV thymidine kinase (TK) gene was deleted and the varicella-zoster virus (VZV) TK gene was introduced into the US5 region under the control of the human cytomegalovirus IE promoter. Infection with the recombinant (R18) led to the induction of TK although the kinetics of synthesis resembled those of a 'late' gene product. The recombinant was virulent in the zosteriform mouse model with the pattern of pathogenesis similar to that of wild-type HSV-1. The sensitivity of the recombinant to several nucleoside analogues was assessed and in most cases (BVaraU, ACV and GCV) it resembled VZV rather than HSV. The enhanced sensitivity of the recombinant to BVaraU compared with wild-type HSV resulted in a far greater response to treatment with BVaraU as assessed in the mouse model.
Bevilacqua
F
F
Deaprtment of Molecular Biology, Wellcome Research Laboratories, Beckenham, Kent, UK.
Davis-Poynter
N
N
Worrallo
J
J
Gower
D
D
Collins
P
P
Darby
G
G
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D003587:Cytomegalovirus / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015774:Ganciclovir / Q000494:pharmacology; D006561:Herpes Simplex / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D014645:Herpesvirus 3, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D014170:Transformation, Genetic; D014774:Virulence; D017735:Virus Latency
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C031368:sorivudine; D013937:Thymidine Kinase; C067854:5-propynylarabinofuranosyluracil; D015774:Ganciclovir; D000212:Acyclovir