Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

Abstract

The replication of herpes simplex virus type 1 (HSV-1) or HSV-2 in MRC-5 cells infected at 0.01 pfu cell−1 treated continuously for 72 h, was inhibited more efficiently by penciclovir than aciclovir ( p = 0.0001). However, multiple cycles of replication were required in order to distinguish the compounds. Virus from cultures treated for 72 h with either compound, at 3 or 10 μg ml−1 was resistant to penciclovir and aciclovir (50% effective concentrations > 10 μg ml−1), but infectivity titres of supernatants from these aciclovirtreated cultures were higher than for penciclovir. Increased production of resistant virus in aciclovirtreated cultures may be the consequence of the less potent inhibition of virus replication by aciclovir. Penciclovir caused prolonged inhibition of HSV-1 and HSV-2 replication in three human cell lines infected at 1 pfu cell−1 following treatment for 18 h, whereas virus replication resumed rapidly after withdrawal of aciclovir. Neither compound showed prolonged activity after 18 h treatment, when the multiplicity of infection was reduced to 0.01 pfu cell−1. This surprising observation prompted experiments testing the effect of repeated pulse treatment in cultures infected at low multiplicity. Penciclovir inhibited HSV-1 replication significantly more effectively than aciclovir in MRC-5 cells infected at 10−4 pfu cell−1 treated daily for 6 h ( p < 0.001, n = 5) but only a trend was observed for HSV-2 ( p = 0.06, n = 6).