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Like other members of the alpha subfamily of herpesviruses, bovine herpesvirus type 1 (BHV-1) establishes latent infections in sensory neurons. BHV-1 induces apoptosis in lymphoid cells in vivo and in epithelial cell lines, but the ability of BHV- 1 to induce apoptosis in sensory neurons remains unknown. In this report, the susceptibility of rabbit ganglionic neurons to infection by BHV-1 was examined in vitro and in vivo. Following infection of cultured neurons with BHV-1, hallmarks of apoptosis such as chromatin condensation, DNA fragmentation and membrane blebbing were detected. The appearance of these changes was preceded by active viral DNA replication as determined by in situ hybridization. When viral DNA replication was blocked by treatment of cultures with an inhibitor of eukaryotic DNA polymerases, apoptosis but not virus attachment to neurons or bICP0 gene expression was completely prevented. Taken together, these results demonstrate that sensory neurons are not intrinsically resistant to BHV-1-induced apoptosis and that viral DNA replication plays a role in triggering the apoptotic program. Infection of rabbits with BHV-1 resulted in pathological changes in the trigeminal ganglia (TG) which included mononuclear cell infiltration and neuronophagia. Morphological evidence of apoptosis was not detected in neurons, even in cells with advanced cytophatology. Furthermore, whereas DNA fragmentation was common in infiltrating cells, it was very rare and sporadic in neurons. Therefore, mechanisms in the TG should exist to prevent neuronal apoptosis upon BHV-1 infection.