The latency-associated transcript (LAT) is the only abundant herpes simplex virus type 1 (HSV-1) transcript expressed during latency. In the rabbit eye model, LAT null mutants do not reactivate efficiently from latency. We recently demonstrated that the LAT null mutant dLAT2903 induces increased levels of apoptosis in trigeminal ganglia of infected rabbits compared to LAT ؉ strains (G. We previously showed that a mutant expressing just the first 1.5 kb of LAT has wild-type spontaneous reactivation in rabbits, and a mutant expressing just the first 811 nucleotides of LAT has a reactivation frequency higher than that of dLAT2903 but lower than that of wild-type virus. In addition, mutants reported here for the first time, expressing just the first 661 or 76 nucleotides of LAT, had spontaneous reactivation indistinguishable from that of the LAT null mutant dLAT2903. In summary, these studies provide evidence that there is a functional relationship between the ability of LAT to promote cell survival and its ability to enhance spontaneous reactivation.-Following ocular, oral, or intranasal infection, herpes simplex virus type 1 (HSV-1) establishes latent infection in trigeminal ganglia (TG) (3, 4). The only abundant viral transcript expressed in latently infected neurons is the latency-associated transcript (LAT) (11,12,32,48,51,54). The primary 8.3-kb primary LAT transcript is unstable and is spliced, yielding an abundant stable 2-kb LAT (12,48,53,56) that is a stable intron (17, 33). LAT is antisense to ICP0 and is primarily localized in the nucleus. This has led to the suggestion that LAT represses ICP0 expression by an antisense mechanism (48), which in turn represses productive infection (8,20). However, we previously showed that the first 1.5 kb of the primary LAT is sufficient for spontaneous reactivation from latency (45). Since this region does not overlap ICP0, antisense repression of ICP0 expression by LAT is not required for spontaneous reactivation in the rabbit model. Although LAT is important for latency in smallanimal models (27,52), its functional roles during the latencyreactivation cycle are not understood.In transient-transfection assays, a LAT fragment (LAT nucleotides 301 to 2659) encompassing the stable 2-kb LAT derived from strain KOS enhanced cell survival following an apoptotic insult (42). The same study also demonstrated that a McKrae LAT Ϫ mutant (dLAT2903) had increased levels of apoptosis in rabbit TG. These findings suggested that LAT is important for latent infections because it promotes survival of infected neurons.HSV-1 can induce or inhibit apoptosis (programmed cell death) in a cell type-dependent manner after infection of cultured cells (1,2,18,19,36). Several antiapoptotic genes have been identified (1,2,18,42), suggesting that regulation of apoptosis is crucial for the virus's life cycle. Trauma, stress, or other imbalances of growth factors or cytokines can induce neuronal apoptosis, and neuronal apoptosis is linked to neurodegenerative disorders (7,21,23,26,35,(38)(39)(40). H...

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The bICP0 protein encoded by bovine herpesvirus 1 (BHV-1) is believed to activate transcription and consequently productive infection. Expression of full-length bICP0 protein is toxic in transiently transfected mouse neuroblastoma cells (neuro-2A) in the absence of other viral genes. However, bICP0 does not appear to directly induce apoptosis. Although bICP0 is believed to be functionally similar to the herpes simplex virus type 1-encoded ICP0, the only protein domain that is well conserved is a C 3 HC 4 zinc ring finger located near the N terminus of both proteins. Site-specific mutagenesis of the zinc ring finger of bICP0 demonstrated that it was important for inducing aggregated chromatin structures in transfected cells and toxicity. The zinc ring finger was also required for stimulating productive infection in bovine cells and for trans-activating the thymidine kinase (TK) promoter of herpes simplex virus type 1. Deletion of amino acids spanning 356-677 of bICP0 altered subcellular localization of bICP0 and prevented trans-activation of the TK promoter. However, this deletion did not prevent trans-activation of the viral genome. Taken together, these studies indicated that bICP0 has several functional domains, including the zinc ring finger, which stimulate productive infection and influence cell survival.

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Bovine herpesvirus 1 (BHV-1) is an important pathogen of cattle and infection is usually initiated via