Acyclovir [9-(2-hydroxyethoxymethyl)
guanine] inhibits Epstein-Barr virus (EBV) replication in lymphoblastoid cells at concentrations nontoxic to cellular growth. The mode of action of the
drug against EBV differs from the mechanism described in herpes simplex virus systems. Due to the absence of virus-specified
thymidine kinase, the
drug is poorly phosphorylated in EBV-infected cells. The extent of monophosphorylation is similar both in mock-infected and EBV-infected cells. Despite weak phosphorylation of the
drug, the replication of linear EBV
DNA is inhibited due to exquisite sensitivity of the
viral DNA polymerase. Activation of
acyclovir does not require phosphorylation by virus-specified
thymidine kinase, inhibition of different herpes-group viruses depends on three variable factors: degree of phosphorylation, cellular metabolism of the
drug, and degree of sensitivity of the viral polymerase. Interaction of
acyclovir-triphosphate with
EBV DNA polymerase is reversible. Cells infected with EBV and treated with
acyclovir resume virus replication following removal of the
drug even after long exposure.
Acyclovir inhibits replication of linear genomes and stops production of virus, but has no effect on latent cellular
infection. These results lead us to predict that
acyclovir will suppress, but not cure,
EBV infection.