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

Abstract

SummaryAfter 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 infectious 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. p primary or initial infections with herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) ~ are clinically indistinguishable. While social habits and other factors contribute to varying sites of initial infections, the predilection of virus to reactivate from specific ganglionic sites maintains the well-known associations of HSV-2 with genital herpes and of HSV-1 with ocular and oral-facial herpes (1, 2). The HSV latency-associated transcripts (LATs) are a family of transcripts specified by the genomic long repeat regions. The more abundant nuclear LAT introns (2.2 kbp in HSV-2 [3-5], 2.0 kbp and 1.5 kbp in HSV-1 [6-9]) are processed via a splicing mechanism from less stable ~8.5-kbp primary LAT transcripts (10). The LATs of HSV-1 and HSV-2 (11-13) are required for efficient reactivation from latency in vivo, but have not been shown to influence acute replication of virus or establishment of latency (14-19) in most 1Abbreviations used in this paper: HSV-1 and HSV-2, herpes simplex virus type 1 and 2; LAT, latency-associated transcript; PI postinoculation; PRK, primary rabbit kidney. animal models, although there is some evidence suggesting an effect on establishment of latency in a mouse model of infection with HSV-1 (20). The sequences of the LAT regions differ significantly between HSV-1 and HSV-2 (4, 21, 22), leading to the hypothesis that differences in the LATs could be responsible for site-specificity of virus recurrence. To test this hypothesis, we introduced an alteration into HSV-2 strain 333 that substituted the LAT region from HSV-1 strain 17syn+ for native HSV-2 LAT sequences, and constructed a rescuant of this mutant. We then tested the ability of parent, mutant, and rescuant viruses to replic...

Herpes simplex virus type-1 latency-associated transcript-induced immunoreactivity of substance P in trigeminal neurons is reversed by bone morphogenetic protein-7

“…The specificity of LAT action on trigeminal neurons may help in understanding the reason that the primary location for latent HSV1 infection is the trigeminal neurons. Our findings are in agreement with the previous report that LAT was found to confer site-specificity of reactivation, and substitution of HSV-1 LAT with HSV-2 LAT sequences resulted in reduction of activation from infected rabbit trigeminal neurons (20).…”

An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor

“…A Ϸ8-kb primary LAT is spliced, yielding a stable Ϸ2-kb LAT intron (2). Deletion of the LAT promoter in both HSV-1 and HSV-2 reduces the efficiency of reactivation (3)(4)(5), and substitution of HSV-1 LAT for native HSV-2 LAT sequences confers an HSV-1 reactivation phenotype (6). The HSV-1 LAT is currently believed to act in part by increasing the establishment or maintenance of latency, likely via an effect on the survival of acutely infected neurons (7), which may be mediated by inhibition of apoptosis in infected neurons (8).…”

Influence of Herpes Simplex Virus Latency-Associated Transcript (LAT) on the Distribution of Latently Infected Neurons

“…Previously in our lab, a chimeric HSV-2 virus expressing the LAT from HSV-1 failed to reactivate efficiently in the guinea pig genital model of HSV infection (114).…”

“…A chimeric HSV-2 virus expressing HSV-1 LAT (HSV-2/LAT1) reactivates from trigeminal ganglia similar to wild type HSV-1 and has a reduced reactivation frequency from lumbosacral ganglia, demonstrating that LAT confers anatomical site-specificity of reactivation (114). This chimera, HSV-2/LAT1, preferentially establishes latency in A5+…”

“…We previously reported on a chimeric virus in which HSV-2 expressed the LAT from HSV-1, including the promoter and sequences extending to near the 3' end of the LAT intron (114). This chimeric virus, HSV-2/LAT1, exhibited a recurrence phenotype more similar to HSV-1 than to HSV-2, with a reduced reactivation frequency from the DRG in the guinea pig genital model and an increased reactivation frequency from TG in the rabbit eye model relative to wild-type HSV-2.…”