The effect of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC) on bovine herpesvirus-1 (BHV-1) infection and reactivation in cattle.

A reproducible pattern of respiratory disease was produced in calves inoculated intranasally with a pathogenic strain of bovine herpesvirus-1 (BHV-1). A latent infection was established which could be reactivated by means of corticosteroid administration. Groups of calves were given a single dose of 20 mg/kg of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC) either the day before or the day following virus inoculation. The drug markedly reduced clinical signs and virus replication; the therapeutic dose appeared to be more effective than the dose given one day before virus inoculation. The establishment of latency was not prevented and a single dose of HPMPC, the day before a course of dexamethasone (6 weeks after the acute infection), did not prevent virus shedding.

The pathogenesis of wild type and drug resistant mutant strains of bovine herpesvirus-1 (BHV-1) in the natural host.

An experimental infection with bovine herpesvirus-1 was established in calves by means of intranasal inoculation. Three calves were infected with the parental strain BHV-1 w/t, three with the TK-defective strain, B 1 and four with the HPMPA-resistant strain, 3 A. Inoculation with w/t virus resulted in a reproducible clinical disease characterised by respiratory distress, fever and the presence of virus in nasal mucus. Following the acute infection, w/t-inoculated animals became seropositive for BHV-1 specific antibody. The TK-defective mutant (BHV-1 B 1) produced an acute infection similar to the parental virus in all three calves inoculated. The HPMPA-resistant mutant (BHV-1 3 A), however, showed a reduced pattern of infection and virus of lower titre was isolated from three of four calves; the antibody responses were generally lower, and one calf remained seronegative until reactivation. Following stimulation with dexamethasone 72 days after the primary inoculation, virus was re-isolated from all wild type-inoculated calves. In contrast, no evidence of reactivation was obtained from the three B 1-inoculated animals. However, all four animals inoculated with the mutant 3 A showed virus reactivation including the calf which had remained seronegative following primary virus inoculation. Previous studies have suggested that drug-resistance mutations in herpesviruses frequently are associated with reduced pathogenicity on the basis of experiments in laboratory models. The importance of the present study is the demonstration that two different drug-resistant variants of an alpha herpesvirus both have altered pathogenicity in the natural host for that infection. These results also have implications for the design and use of attenuated vaccine strains.