title: Herpes simplex virus latency-associated transcript sequence downstream of the promoter influences type-specific reactivation and viral neurotropism.
abstract: Herpes simplex virus (HSV) establishes latency in sensory nerve ganglia during acute infection and may later periodically reactivate to cause recurrent disease. HSV type 1 (HSV-1) reactivates more efficiently than HSV-2 from trigeminal ganglia while HSV-2 reactivates more efficiently than HSV-1 from lumbosacral dorsal root ganglia (DRG) to cause recurrent orofacial and genital herpes, respectively. In a previous study, a chimeric HSV-2 that expressed the latency-associated transcript (LAT) from HSV-1 reactivated similarly to wild-type HSV-1, suggesting that the LAT influences the type-specific reactivation phenotype of HSV-2. To further define the LAT region essential for type-specific reactivation, we constructed additional chimeric HSV-2 viruses by replacing the HSV-2 LAT promoter (HSV2-LAT-P1) or 2.5 kb of the HSV-2 LAT sequence (HSV2-LAT-S1) with the corresponding regions from HSV-1. HSV2-LAT-S1 was impaired for reactivation in the guinea pig genital model, while its rescuant and HSV2-LAT-P1 reactivated with a wild-type HSV-2 phenotype. Moreover, recurrences of HSV-2-LAT-S1 were frequently fatal, in contrast to the relatively mild recurrences of the other viruses. During recurrences, HSV2-LAT-S1 DNA increased more in the sacral cord compared to its rescuant or HSV-2. Thus, the LAT sequence region, not the LAT promoter region, provides essential elements for type-specific reactivation of HSV-2 and also plays a role in viral neurotropism. HSV-1 DNA, as quantified by real-time PCR, was more abundant in the lumbar spinal cord, while HSV-2 DNA was more abundant in the sacral spinal cord, which may provide insights into the mechanism for type-specific reactivation and different patterns of central nervous system infection of HSV-1 and HSV-2.
authors.affiliation: Uniformed Services University of the Health Sciences, Bethesda, MD 20892-4555, USA.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Bertke
authors.forename: Amita
authors.initials: A
authors.lastname: Patel
authors.forename: Philip R
authors.initials: PR
authors.lastname: Krause
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000821:virology*; D006168:Guinea Pigs; D035683:MicroRNAs; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics*; D017735:Virus Latency
chemical_list: D004279:DNA, Viral; D035683:MicroRNAs; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C477253:latency associated transcript, herpes simplex virus-1