Scientific Publications by FDA Staff

J Virol 2007 Jun;81(12):6605-1

Herpes Simplex Virus Latency-Associated Transcript (LAT) Sequence Downstream of the Promoter Influences Type-Specific Reactivation and Viral Neurotropism.

Bertke AS, Patel A, Krause PR

Krause PR (reprint author), CBER, FDA, HFM-457,29 Lincoln Dr, Bethesda, MD 20892 USA CBER, FDA, Bethesda, MD 20892 USA Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA

Herpes simplex virus (HSV) establishes latency in sensory nerve ganglia during acute infection and may later periodically reactivate to cause recurrent disease. HSV-1 reactivates more efficiently from trigeminal ganglia while HSV-2 reactivates more efficiently from lumbosacral dorsal root ganglia (DRG) to cause recurrent orofacial and genital herpes, respectively. In a previous study, a chimeric HSV-2 virus 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 than in the DRG over latent levels 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 CNS infection of HSV-1 and HSV-2.