Acyclovir inhibition of Epstein-Barr virus replication.

Abstract

Acyclovir [92-hydroxyethoxymethyl)guanineJ triphosphate inhibits Epstein-Barr virus (EBV)associated DNA polymerase (DNA nucleotidyltransferase; EC 2.7.7.7) to a greater extent than it inhibits host a and jB DNA polymerases. The affinity of the compound for viral polymerase is 100-fold higher than for a-polymerase. Selective prevention of virus replication can be attained by compounds that inactivate the novel enzymes necessary for virus growth. Virus-specific DNA polymerase (deoxynucleoside triphosphate:DNA nucleotidyltransferase, EC 2.7.7.7) is one of the target enzymes most suitable for this purpose (1-3). Several nucleoside analogs inhibit virus replication by affecting this enzyme (4-9). Acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] is one of a class of antiviral compounds recently shown to be effective in a variety of herpesvirus infections in vitro and in animal models (10). In both herpes simplex virus (HSV) type I and type II systems the drug is highly effective with an ED50 (effective dose required for 50% inhibition) of 0.1-0.2 AM without adverse effect on the host cells.Studies on the mechanism of action of this compound in HSV systems have shown that the drug is phosphorylated by the virus-specified thymidine kinase to its monophosphate form, which is subsequently converted to triphosphate by the host enzyme systems (11, 12). The triphosphorylated form of this compound inhibits viral DNA synthesis by inhibiting viral DNA polymerase by competing with dGTP (13). Results have been presented to suggest that the drug is incorporated into HSV DNA chains and thus terminates viral DNA synthesis (13). Recent genetic experiments also suggest that at least two virally coded functions, namely, virus-specific thymidine kinase and DNA polymerase, are responsible for the action of acyclovir in HSV-infected cells (14,15).The compound is also effective in inhibiting Epstein-Barr virus (EBV) replication at drug-dosage levels (6-7 ,uM) The present studies show that acyclovir triphosphate inhibits EBV-associated DNA polymerase to a much greater extent than it inhibits host a-and /3-polymerases. The triphosphorylated form of the drug behaves as a classical competitive inhibitor of EBV DNA polymerase with respect to dGTP. The concept that the action of this drug is reversible is further supported by the fact that the virus-producing cells (P3HR-1) exposed to the drug over a long period of time show lowered levels of viral capsid antigen (VCA) and viral genome numbers that return to control levels with the removal of the drug. These observations, coupled with the apparent inefficient phosphorylation of ACV in EBV-infected cells (unpublished results), in contrast to the striking and selective phosphorylation in HSV-infected cells (11,12), lead us to propose that the high sensitivity of EBVassociated DNA polymerase towards ACV triphosphate accounts for the inhibition of EBV replication. In this case a small amount of phosphorylated drug, phosphorylated perhaps by host thymidine or purine nucleoside kinases, is...

Inhibition of the Epstein-Barr Virus Lytic Cycle by Andrographolide

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The Effect of Acyclovir on the Acute and Latent Murine Gammaherpesvirus-68 Infection of Mice

“…Furthermore. ACV can inhibit EBV replication in superinfected Raji or EBV virus producer Iymphoblastoid cell lines (Datta et al, 1980;Colby et al, 1981). These studies have shown that ACV can be used to distinguish between latent and chronic persistence and is therefore an important tool in studying the mechanisms of persistence of herpesviruses.…”

The Epstein-Barr Virus (EBV)-Encoded Protein Kinase, EBV-PK, but Not the Thymidine Kinase (EBV-TK), Is Required for Ganciclovir and Acyclovir Inhibition of Lytic Viral Production

“…During the lytic form of viral replication, EBV uses a virally encoded DNA polymerase and the oriLyt replication origin to duplicate its genome (24,36,51). The lytic form of EBV replication can be effectively inhibited in vitro by the guanine nucleoside analogues, acyclovir (ACV) and ganciclovir (GCV) (11,16,50,56). Since acyclovir is significantly less toxic than ganciclovir in patients, acyclovir is generally used to treat diseases associated with lytic EBV infection, such as oral hairy leukoplakia (3).…”