9-(4-HYDROXYBUTYL)-N-2-PHENYLGUANINE (HBPG), A THYMIDINE KINASE INHIBITOR, SUPPRESSES HERPES-VIRUS REACTIVATION IN MICE

In cells of the nervous system, which have little or no cellular thymi dine kinase, the pharmacologic inhibition of viral thymidine kinase ma y prevent the reactivation of herpes virus, which requires phosphoryla ted thymidine for replication. We tested a newly synthesized inhibitor of viral thymidine kinase, 9-(4-hydroxybutyl)-N-2-phenylguanine (HBPG ) for its capacity to suppress the reactivation of herpes simplex viru s type 1 (HSV-1) in vivo. Mice, latently infected with McKrae strain H SV-1, were treated with intraperitoneal injections of HBPG in a corn o il vehicle (200 mg/kg every 3 h for a total of ten doses), and subject ed to hyperthermic stress to stimulate viral reactivation immediately before the third treatment. Three h after the last treatment, the mice were sacrificed, and the presence of infectious virus was determined by culture of ocular surface swabs and trigeminal ganglionic homogenat es. Additionally, viral DNA in ganglionic extracts was analyzed by qua ntitative PCR. Controls included latently infected, stressed animals r eceiving injections of corn oil vehicle only, and latently infected, d rug- and vehicle-treated, unstressed animals. HBPG had a statistically significant inhibitory effect on hyperthermia-induced viral reactivat ion. Homogenates of trigeminal ganglia and ocular surface swabs from H BPG-treated animals were less likely to contain infectious virus than those of infected, vehicle-treated, stressed controls (P < 0.005, ANOV A). Unstressed controls showed no reactivation. Quantitation of viral DNA in ganglionic extracts demonstrated a 100-fold reduction in the am ount of viral DNA in the ganglia of HBPG-treated animals, compared wit h vehicle-treated controls (P < 0.05, ANOVA). The results indicate tha t HBPG has an inhibitory effect when given systemically for the suppre ssion of herpes virus reactivation in mice.