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Journal of Virology, June 2007, p. 6605-6613, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02701-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Latency-Associated Transcript Sequence Downstream of the Promoter Influences Type-Specific Reactivation and Viral Neurotropism{triangledown}

Andrea S. Bertke,1,2 Amita Patel,2 and Philip R. Krause1,2*

Uniformed Services University of the Health Sciences, Bethesda, Maryland,1 FDA/CBER, Bethesda, Maryland2

Received 7 December 2006/ Accepted 23 March 2007

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.

* Corresponding author. Mailing address: FDA/CBER, HFM-457, 29 Lincoln Drive, Bethesda, MD 20892-4555. Phone: (301) 827-1914. Fax: (301) 496-1810. E-mail: philip.krause{at}fda.hhs.gov

{triangledown} Published ahead of print on 4 April 2007.

Journal of Virology, June 2007, p. 6605-6613, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02701-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bertke, A. S., Patel, A., Imai, Y., Apakupakul, K., Margolis, T. P., Krause, P. R. (2009). Latency-Associated Transcript (LAT) Exon 1 Controls Herpes Simplex Virus Species-Specific Phenotypes: Reactivation in the Guinea Pig Genital Model and Neuron Subtype-Specific Latent Expression of LAT. J. Virol. 83: 10007-10015 [Abstract] [Full Text]  
  • Imai, Y., Apakupakul, K., Krause, P. R., Halford, W. P., Margolis, T. P. (2009). Investigation of the Mechanism by Which Herpes Simplex Virus Type 1 LAT Sequences Modulate Preferential Establishment of Latent Infection in Mouse Trigeminal Ganglia. J. Virol. 83: 7873-7882 [Abstract] [Full Text]  
  • Tang, S., Bertke, A. S., Patel, A., Wang, K., Cohen, J. I., Krause, P. R. (2008). An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor. Proc. Natl. Acad. Sci. USA 105: 10931-10936 [Abstract] [Full Text]  


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