The characteristic site-specific reactivation phenotypes of HSV-1 and HSV-2 depend upon the latency-associated transcript region.

After replication at sites of initial inoculation, herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) establish lifelong latent infections of the sensory and autonomic neurons of the ganglia serving those sites. Periodically, the virus reactivates from these neurons, and travels centripetally along the neuronal axon to cause recurrent epithelial infection. The major clinically observed difference between infections with herpes simplex virus type 1 and type 2 is the anatomic site specificity of recurrence. HSV-1 reactivates most efficiently and frequently from trigeminal ganglia, causing recurrent ocular and oral-facial lesions, while HSV-2 reactivates primarily from sacral ganglia causing recurrent genital lesions. An intertypic recombinant virus was constructed and evaluated in animal models of recurrent ocular and genital herpes. Substitution of a 2.8-kbp region from the HSV-1 latency-associated transcript (LAT) for native HSV-2 sequences caused HSV-2 to reactivate with an HSV-1 phenotype in both animal models. The HSV-2 phenotype was restored by replacing the mutated sequences with wild-type HSV-2 LAT-region sequences. These sequences or their products must act specifically in the cellular environments of trigeminal and sacral neurons to promote the reactivation patterns characteristic of each virus.

Expression of the herpes simplex virus type 2 latency-associated transcript enhances spontaneous reactivation of genital herpes in latently infected guinea pigs.

The 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.

Quantity of latency-associated transcript produced by herpes simplex virus is not predictive of the frequency of experimental recurrent genital herpes.

The role of the latency-associated transcript (LAT) in control of recurrent herpes simplex virus type 2 (HSV-2) infection was investigated by examining whether LAT concentration in vitro during productive infection or in ganglia during latency correlated with frequency of recurrent genital herpes. Clinical HSV-2 isolates from frequent or infrequent recurrent genital disease produced comparable amounts of glycoprotein D and infected cell polypeptide 0 RNA, but the isolate from frequent disease produced about seven times more LAT. The guinea pig model of genital herpes was used to determine whether the quantity of LAT produced during acute infection in vitro correlated with recurrence phenotype; the frequency of recurrent disease was similar for the 2 clinical isolates. Likewise, there was no correlation between the recurrence phenotype of individual animals and LAT concentration in their ganglia. Thus, while absence of LAT may impair HSV reactivation and recurrence, once a threshold concentration is exceeded, LAT has no further effect on recurrence frequency.