AN OVERVIEW OF THE FURTHER EVALUATION OF PENCICLOVIR AGAINST HERPES-SIMPLEX VIRUS AND VARICELLA-ZOSTER VIRUS IN CELL-CULTURE HIGHLIGHTING CONTRASTS WITH ACYCLOVIR

The antiviral action of penciclovir against herpes simplex virus (HSV) and varicella-zoster virus (VZV) in cell culture is reviewed. Acyclov ir was included for comparison in most of the experiments described. W hilst these two acyclic nucleoside derivatives share a mode of action which is qualitatively similar, quantitative differences were revealed in certain cell culture experiments, and the objective of subsequent biochemical studies was to account for these differences. Where possib le, the conditions selected for the cell culture experiments were clin ically relevant. The relative antiviral activities of penciclovir and acyclovir were compared using four distinct assays against a single st rain of HSV-1 in MRC-5 cells. Some differences in relative potency wer e observed between the assays and possible reasons for this are discus sed. In a subsequent study the initial multiplicity of infection (MOI) was shown to be inversely related to the potency of penciclovir again st HSV-1 in both a virus-yield reduction assay and an antigen-inhibiti on assay, although this relationship was not observed in the viral DNA inhibition assay. Because the determination of infectious virus yield s was considered to be a particularly useful measure of antiviral effi cacy, further virus yield experiments were conducted. Consistently bet ter activity was observed with penciclovir in a series of experiments with clinical isolates of HSV-1 and HSV-2 in which MRC-5 cells were tr eated continuously with test compounds following infection at 0.01 p.f .u. cell-1. Furthermore, marked differences were observed between penc iclovir and acyclovir when the treatment period was reduced to as litt le as 2 h and effects on subsequent infectious virus replication or vi ral DNA synthesis were monitored; unlike acyclovir, there was prolonge d inhibition of HSV replication in cultures which had been exposed to penciclovir for short periods. The triphosphate of penciclovir is cons iderably more stable than acyclovir-triphosphate within HSV-infected c ells, and therefore this difference probably accounts for the prolonge d antiviral activity observed in cell culture. Prolonged inhibition of VZV DNA synthesis by penciclovir is also reported in this review. Fin ally, the antiviral activity of combinations of penciclovir with other antiviral agents or with human interferons (HuIFN-alpha,beta,gamma) i s reviewed. There was marked synergy between penciclovir and HuIFN-alp ha and HuIFN-beta against HSV-1 and HSV-2 and possible clinical implic ation of these results are discussed.