SunllnaryThe latency-associated transcript (LAT) is the only herpes simplex virus (HSV) gene product detectable in latently infected humans and animals. In this report, we show that a 624-bp deletion in the promoter of the HSV-2 LAT had no discernable effect on viral growth in tissue culture or in acute genital infection of guinea pigs, but impaired LAT accumulation and led to a marked decrease in spontaneous genital recurrences when compared with the behavior of wild-type and rescuant strains. Differences in the ability of the mutant to replicate, or in how readily it established or maintained latency did not account for this finding. Thus, HSV LAT expression facilitates the spontaneous reactivation of latent virus.fter replication at sites of initial inoculation, herpes simplex virus types 1 and 2 (HSV-1 and -2) 1 establish lifelong latent infections of the sensory neurons of the ganglia serving those sites. Periodically, the virus reactivates, and travels centripetally along the neuronal axon to cause symptomatic or asymptomatic recurrent mucocutaneous infections (1, 2). While many factors may influence the likelihood of a reactivation giving rise to a recurrent lesion, considerable interest has been focused recently on the molecular mechanisms of reactivation.Of the more than 75 HSV genes, only the latency-associated transcripts (LATs) are known to be expressed during latency (3, 4). The LATs are transcribed from within the long repeats of the viral genome, and consist of both an 8-9-kb "minor LAT" species (5, 6), and the abundant "major LATs" (of about 1.9 and 1.5 kb in HSV-1 [%10] or of 2.2 kb in HSV-2 [11-13]; see Fig. 1) which appear to be processed from the minor species (14). The major LATs overlap the 3' terminus of the viral immediate-early transactivator ICP0 in an antisense direction. The minor LATs extend even further, overlapping not only the ICP0 gene but also the gene encoding the neurovirulence I Abbreviations used in thispalx.r: HSV-1 and -2, herpes simplex virus types I and 2; LAT, htency-associated transcripts; MOI, multiplicity of infection; UL, unique long. protein ICP34.5 and possibly the 3' end of the gene for ICP4, which encodes another immediate-early regulatory protein.Promoter sequences required for LAT transcription during latency reside upstream of the minor LAT (15-17). Studies of latently infected animals and humans have revealed no evidence for the translation of the LAT into a protein product. While HSV-1 and HSV-2 are genetically related viruses, and both encode LATs, the sequences of the HSV-1 and HSV-2 major LATs share essentially random homology throughout the major LAT sequences (12,18,19).In humans, spontaneous reactivation of latent virus results in recurrent disease. Whereas several animal models have been used to study HSV-1 latency and the role of the LATs in the pathogenesis of infection, there is no model of latent HSV-1 infection in which spontaneous reactivation produces recurrent lesions. Hence, studies to define the effect of LAT expression on HSV-1 reactivatio...