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

doi:10.1084/jem.184.2.659

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

T Yoshikawa, JM Hill, LR Stanberry, N Bourne, JF Kurawadwala and PR Krause
Division of Viral Products, Food and Drug Administration, Bethesda, Maryland, USA.

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.
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