SELECTIVE INHIBITION OF THE REPLICATION OF VARICELLA‐ZOSTER VIRUS BY 5‐HALOGENATED ANALOGS OF DEOXYCYTIDINE *

Varicella-zoster is a classic example of the latent nature of many herpesvirus infections. The first exposure of an individual to the varicella-zoster or V Z virus results in the disease chickenpox or varicella. The virus then appears to remain in the individual in a latent or masked state. Certain factors apparently induce the reactivation of this latent virus to produce shingles or herpes zoster. Both of these clinical entities are usually self-limiting.' The infection can become widely disseminated, however, leading to severe life-threatening disease in cancer patients, transplant recipients receiving immunosuppressive therapy, and patients undergoing treatment with various chemotherapeutic agents.2-5 To date, a number of agents have been evaluated for their efficacy against herpes zoster. Some success has been reported with 5-iododeoxyuridine administered with dimethyl sulphoxide.6 On the other hand, cytosine arabinoside was without value in the treatment of localized' and disseminatedX herpes zoster. A recent report has demonstrated that low-dosage cytosine arabinoside infusion was effective in the treatment of disseminated herpes zoster with p n e ~ m o n i a . ~ Preliminary trials suggest that adenine arabinoside may be beneficial in the therapy of herpes zoster.'O Previous studies in this laboratory have demonstrated that 5-bromodeoxycytidine (BrdC) and iododeoxycytidine (IdC) can serve as selective chemotherapeutic agents in cells infected with herpes simplex virus types I and 2."." Furthermore, studies with an experimental mouse encephalitis system have demonstrated the antiviral potential of BrdC.I2 Infection of cells with either virus results in the induction of a virus-specific pyrimidine deoxyribonucleoside kinase which is capable of phosphorylating BrdC;13 in contrast, BrdC is a poor substrate for host cell thymidine (dT) kinaseI4 and deoxycytidine (dC) k i n a ~ e . ' ~ . ~ ~ Since phosphorylation must occur prior to further utilization of the BrdC, the active inhibitory state is present only in infected cells and not in uninfected cells. We have expanded the original studies to include other clinically important members of the herpesvirus group. This report describes experiments that demonstrate that varicella-zoster virus, by inducing a pyrimidine deoxyribonucleoside kinase with a substrate specificity similar to that induced by herpes simplex virus, is selectively inhibited by BrdC. These studies have been performed with the Flow 2000 strain of human embryonic lung (HEL) cells. We have used the Ellen strain of varicella-zoster virus from