The earliest events within the peripheral mammalian nervous system that cause herpes simplex virus type 1 (HSV-1) to reactivate from latency are unknown but are highly likely to include altered regulation of cellular transcription factors. Using gene array analysis, we have examined the changes that occur in cellular mRNA levels in mouse trigeminal ganglia following explantation, a stimulus that results in HSV-1 reactivation from latency. We have detected both increased and decreased expression levels of particular cellular transcripts, which include RNAs encoding neuronal factors, transcription factors, and factors involved in the cell cycle. Among the transcription factors that are upregulated is Bcl-3, a coactivator for NFB. We have confirmed these increases in Bcl-3 transcription levels using reverse transcription-PCR and S1 nuclease protection assays. In addition, we have shown Bcl-3 upregulation at the protein level. Importantly, Bcl-3 RNA levels were found to increase specifically in neuronal cells within the trigeminal ganglia. We discuss a potential role for this factor in upregulating ICP0 transcription, which is an important viral event for initiation of HSV-1 reactivation.Following primary infection, herpes simplex virus (HSV) establishes a latent state within neurons of sensory ganglia. During latency, episomal HSV genomes are generally inactive, with viral transcription mainly from the latency-associated transcripts, although low levels of certain immediate-early (IE) and early (E) transcripts have been detected (18, 37). The virus can undergo periodic reactivation leading to recurrent disease in response to certain stimuli, such as stress, tissue damage, or the presence of immune system modulators, neurotransmitters, hormones, or growth factors (19,20,55). Similar to primary infection, the reactivation process includes several steps leading to the release of complete viral particles, including transcription of viral (IE and E) genes and replication of the viral DNA.The temporal pattern of HSV gene expression during primary infection in tissue culture is well documented (28, 29). The initial event is IE transcription, mediated by the cellular transcription factors Oct-1 and HCF functioning in a complex with the viral transactivator VP16 (a virion protein) through binding to TAATGARAT upstream sequences (52, 61). The IE gene products are transcription factors that promote E and late (L) gene expression. It has been shown that this cascade of viral gene expression is not seen during the reactivation process. Rather, IE and E transcripts are both detected at the earliest times of reactivation and the onset of their expression is simultaneous (63). Since VP16 is not expressed in latently infected neurons and moreover is not required for reactivation from ganglionic explants (60), it is likely that viral transcription is initiated during reactivation by endogenous factors expressed from these tissues. Candidates for this function are cellular factors that regulate the HSV type 1 (HSV-1) genome, either b...