INHIBITORS OF BOVINE HERPES MAMMILLITIS VIRUS-INFECTIONS IN CULTURED-CELLS AND IN VAGINALLY INFECTED GUINEA-PIGS

Bovine herpes mammillitis virus or bovine herpesvirus type 2 (BHV-2) c auses ulcerative lesions on the teats and udders of infected cows. The authors investigated several nucleoside and nucleotide analogues as p otential BHV-2 inhibitors. These included acyclovir, ganciclovir, 5-io do-2'-deoxyuridine (IUdR), 1-(2'deoxy-2'-fluoro-beta-D-arabinofuranosy l) derivatives of 5-iodocytosine (FIAC), 5-iodouracil (FIAU), and 5-me thyluracil (FMAU), and various 3-hydroxyphosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of adenine (A), guanin e (G), 2,6-diaminopurine (DAP), and/or cytosine (C). Of these, FIAU an d FMAU were the most potent in cell culture, inhibiting 50% of BHV-2 p laques at <0.05 mu M. HPMPA and HPMPG were active at 0.3 mu M; FIAC, I UdR and HPMPC at 1.3-2.3 mu M; PMEDAP and ganciclovir at 20-25 mu M; a cyclovir and PMEA at >100 mu M. The two most potent agents, FIAU and F MAU, inhibited uninfected embryonic bovine tracheal cell growth by 50% at >100 mu M and 53 mu M, respectively, resulting in selectivity indi ces (ratio of the 50% inhibitory concentration for cell growth to the 50% inhibitory concentration for plaque formation) of >2200 and 1100. Greater degrees of antiviral activity and selectivity were obtained in infected guinea pig embryo cells treated with FIAU, FMAU, and HPMPC. Infected cell extracts containing BHV-2-induced thymidine kinase activ ity phosphorylated FIAU, FMAU, and IUdR at nearly the same rate as thy midine, whereas FIAC, acyclovir, and ganciclovir were phosphorylated a t less than or equal to 5% the rate of thymidine. Phosphorylation by t his enzyme is required to generate the antivirally active nucleoside t riphosphate with BHV-2, FMAU treatments of 1,3.2, and 10mg kg(-1) per day for 5 days starting 1 day after virus challenge reduced vaginal le sion scores and virus titres in a dose-dependent manner. FIAU (10 mu M ) was as effective as 1 mu M FMAU by the same regimen. A single treatm ent with 10 mu M HPMPC was as active as daily treatments with 3.2mg FM AU kg(-1). These results indicate the potential of using antiviral age nts to treat bovine herpes mammillitis virus infections in cattle, and the application of guinea pigs to study BHV-2 disease.