A Gene Capable of Blocking Apoptosis Can Substitute for the Herpes Simplex Virus Type 1 Latency-Associated Transcript Gene and Restore Wild-Type Reactivation Levels

Abstract

Herpes simplex virus type 1 (HSV-1) is a large (152-kb) double-stranded DNA virus with neurotropic properties. HSV-1 establishes lifelong latent infections in host sensory neurons. This virus is wide spread in the general population. When the eye is infected, the virus travels up nerves and establishes latent infection in neurons of the trigeminal ganglia (TG). During neuronal latency, HSV-1 has no apparent impact on the infected individual. The latent virus can reactivate at various times throughout the life of the individual. This occurs through a mechanism(s) that is currently not completely understood. HSV-1 reactivation in the TG results in virus returning to the eye via the same route previously used to get from the eye to the TG. At the eye, reactivated HSV-1 can produce recurrent disease. Recurrent HSV-1 infection in the eye can cause corneal scarring leading to loss of vision. As a result, HSV-1 is one of the most common infectious causes of corneal blindness in the developed world.During neuronal latency, LAT (latency-associated transcript) is the only abundantly transcribed viral gene (30, 37). The primary LAT transcript is ca. 8.3 kb long (7, 45) and overlaps two viral genes, ICP0 and ICP34.5, in an antisense direction (30,37). A very stable intron, the 2-kb LAT is spliced from the primary transcript (9) and is the major LAT RNA detected during latency (7,33,36,(42)(43)(44).LAT enhances the induced and spontaneous reactivation phenotypes in the rabbit ocular model (12, 21) and the induced reactivation phenotype in mice (1a, 6, 19, 26, 31, 35). The reduced reactivation phenotypes of LAT Ϫ mutants does not necessarily imply that LAT is directly involved in the molecular mechanism of HSV-1 reactivation from latency. LAT might enhance reactivation by increasing the initial amount of latency established and/or by maintaining a high level of latently infected neurons. The larger pool of latently infected neurons and/or the larger pool of neurons containing high copy numbers of the HSV-1 genome would be expected to increase reactivation. Several reports have, in fact, shown that in experimentally infected animals more neurons become latently infected with LAT ϩ viruses compared to LAT Ϫ viruses (29,31,40). In addition, we have recently shown that LAT has anti-* Corresponding author. Mailing address:

Bovine herpesvirus 1 infection and infectious bovine rhinotracheitis

“…The BoHV-1 LRT mutants were not re-excreted following a reactivation treatment with dexamethasone, which induced reactivation and re-excretion in all calves infected by either wild-type or LRT rescued virus [81]. Moreover a chimeric HSV-1 mutant where the BoHV-1 LR gene replaces the deleted Latency Associated Transcript locus of HSV-1 presents a high level of spontaneous reactivation in the rabbit eye model [159]. Altogether, these results indicate that the LR gene is required for the BoHV-1 latency-reactivation cycle.…”

Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels

“…Consequently, LAT can inhibit caspase 8-or caspase 9-induced apoptosis (Henderson et al, 2002;Jin et al, 2003;Peng et al, 2004), the two major apoptotic pathways (Krueger et al, 2001;Schmitz et al, 2000;Wang, 2001). The anti-apoptosis functions of LAT correlate with promoting spontaneous reactivation (Inman et al, 2001;Jin et al, 2003) and appear to be the crucial function of LAT because three different anti-apoptosis genes restore wt levels of spontaneous reactivation to a LAT null mutant virus (Jin et al, 2005(Jin et al, , 2008Mott et al, 2003;Perng et al, 2002b). LAT also represses productive viral gene expression in TG of mice during acute infection (Chen et al, 1997b;Garber et al, 1997).…”

Herpes Simplex Virus Latency-Associated Transcript Gene Function

“…Interestingly, these LAT sequences correspond to regions used in expression plasmids to demonstrate the LAT's ability to convey protection from apoptoticinducing agents (Inman et al, 2001). The latencyrelated gene of bovine herpes virus 1, which also has been shown to possess antiapoptotic characteristics, can recover the spontaneous reactivation phenotype of a LAT-null mutant (Perng et al, 2002). These associations lead to speculation of a correlation between the LATs' antiapoptotic ability and the role of the LATs in reactivation of the virus, although the apoptotic mapping data would suggest that the LAT exon rather than the intron is the functional molecule.…”