An Overview of the Further Evaluation of Penciclovir against Herpes Simplex Virus and Varicella-Zoster Virus in Cell Culture Highlighting Contrasts with Acyclovir

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Abstract
The antiviral action of penciclovir against herpes simplex virus (HSV) and varicella-zoster virus (VZV) in cell culture is reviewed. Acyclovir was included for comparison in most of the experiments described. Whilst 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 possible, the conditions selected for the cell culture experiments were clinically relevant. The relative antiviral activities of penciclovir and acyclovir were compared using four distinct assays against a single strain of HSV-1 in MRC-5 cells. Some differences in relative potency were observed between the assays and possible reasons for this are discussed. In a subsequent study the initial multiplicity of infection (MOI) was shown to be inversely related to the potency of penciclovir against HSV-1 in both a virus-yield reduction assay and an antigen-inhibition assay, although this relationship was not observed in the viral DNA inhibition assay. Because the determination of infectious virus yields was considered to be a particularly useful measure of antiviral efficacy, further virus yield experiments were conducted. Consistently better 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 treated continuously with test compounds following infection at 0.01 p.f.u. cell−1. Furthermore, marked differences were observed between penciclovir and acyclovir when the treatment period was reduced to as little as 2 h and effects on subsequent infectious virus replication or viral DNA synthesis were monitored; unlike acyclovir, there was prolonged inhibition of HSV replication in cultures which had been exposed to penciclovir for short periods. The triphosphate of penciclovir is considerably more stable than acyclovir-triphosphate within HSV-infected cells, and therefore this difference probably accounts for the prolonged antiviral activity observed in cell culture. Prolonged inhibition of VZV DNA synthesis by penciclovir is also reported in this review. Finally, the antiviral activity of combinations of penciclovir with other antiviral agents or with human interferons (HuIFN-α, β, γ) is reviewed. There was marked synergy between penciclovir and HuIFN-α and HuIFN-β against HSV-1 and HSV-2 and possible clinical implication of these results are discussed.