Efficacy of 5-Vinyl-l-β-D-arabinofuranosyluracil (VaraU) Against Herpes Simplex Virus Type 2 Strains in Cell Cultures and Against Experimental Herpes Encephalitis in Mice: Comparison with Acyclovir and Foscarnet

The sensitivity of different herpes simplex virus type 2 (HSV-2) strains to inhibition by 5-vinyl-l-β-D-arabinofuranosyluracil (VaraU) was evaluated in comparison to 9-(2-hydroxyethoxymethyl)guanine (ACV; acyclovir) and trisodiumphosphonoformate (Na3PFA; foscarnet), using a plaque inhibition assay in primary rabbit testes (PRT) cells as well as in human embryonic lung fibroblast (HELF) cell cultures. The order of decreasing activity found was ACV ≫ VaraU > Na3PFA in PRT cells and ACV > VaraU ≫ Na3PFA in HELF cells, with 50% inhibition doses (ID50) of 1.8, 8.8, and >110 µM for the three drugs in HELF cells, respectively. After 72hr of drug treatment, inhibition of HELF cell proliferation by VaraU (ID50, >1000 µM) was less than that by ACV and Na3PFA, resulting in high selectivity indexes of >100 against HSV-2 for VaraU and ACV. Their in vivo efficacy was assessed in a mouse encephalitis model. Using a treatment schedule of three daily intraperitoneal (ip) doses over a period of 5 days, only the survival times of mice were considerably prolonged by VaraU (150 or 300 mg/kg per day; P < 0.05 or P < 0.001, respectively). In contrast, ACV treatment (150 mg/kg per day) led to a nearly complete prevention of encephalitis and death (P < 0.001). Similar therapy results with VaraU application through the drinking water were obtained using only one-sixth of the high ip dose (∼50 mg/kg per day) but over a prolonged period of treatment. Under similar conditions no therapeutic effect of oral Na3PFA was observed.