Intranasal inoculation of the rabbit was shown to be a viable alternative to eye inoculation as a model to study latency and reactivation of bovine herpesvirus 1 (BHV-1). In four different experiments, separate groups of rabbits were intranasally inoculated with BHV-1. In two experiments some rabbits were inoculated instead with a TK-defective (TK-) mutant strain of BHV-1. The development of a specific antibody response was monitored by both virus neutralization and ELISA assays. Cell-mediated immunity was measured by means of a skin test. Many weeks after virus inoculation the rabbits were treated with corticosteroid. Antibody formation after treatment was markedly different in wild type and in TK- virus inoculated groups. In the former, virus reactivation was suggested by a sudden rise in serum antibody levels with kinetics closely resembling those reported in infected calves following corticosteroid administration, whereas in the case of the TK- group no significant increase in antibody activity was measured. Histopathological changes in trigeminal ganglia also indicated reactivation of virus in the wild-type virus infected animals. Further evidence for reactivation was obtained by virus isolation from nasal swabs after corticosteroid treatment.
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.
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