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Journal of Virology, March 2001, p. 2912-2920, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2912-2920.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inducible Cyclic AMP Early Repressor Produces Reactivation of Latent Herpes Simplex Virus Type 1 in Neurons In Vitro

Mark A. Colgin,1 Roderic L. Smith,2 and Christine L. Wilcox1,*

Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523,1 and Departments of Neurology and Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 802622

Received 30 August 2000/Accepted 20 December 2000

Herpes simplex virus type 1 (HSV-1) establishes a latent infection in neurons of the peripheral nervous system. During latent HSV-1 infection, viral gene expression is limited to latency-associated transcripts (LAT). HSV-1 remains latent until an unknown mechanism induces reactivation. The ability of the latent virus to periodically reactivate and be shed is essential to the transmission of disease. In vivo, the stimuli that induce reactivation of latent HSV-1 include stress, fever, and UV damage to the skin at the site of initial infection. In vitro, in primary neurons harboring latent HSV-1, nerve growth factor (NGF) deprivation or forskolin treatment induces reactivation. However, the mechanism involved in the induction of reactivation remains poorly understood. An in vitro neuronal model of HSV-1 latency was used to investigate potential mechanisms involved in the induction of reactivation of latent HSV-1. In situ hybridization analysis of neuronal cultures harboring latent HSV-1 showed a marked, rapid decrease in the percentage of LAT-positive neurons following induction of reactivation by NGF deprivation or forskolin treatment. Western blot analysis showed a corresponding increase in expression of the cellular transcription factor inducible cyclic AMP early repressor (ICER) during reactivation. In transient-transfection assays, ICER downregulated LAT promoter activity. Expression of ICER from a recombinant adenoviral vector induced reactivation and decreased the percentage of LAT-positive neurons in neuronal cultures harboring latent HSV-1. These results indicate that ICER represses LAT expression and induces reactivation of latent HSV-1.

* Corresponding author. Mailing address: Colorado State University, Department of Microbiology, Fort Collins, CO 80523. Phone: (970) 491-2552. Fax: (970) 491-1815. E-mail: cwilcox{at}cvmbs.colostate.edu.

Journal of Virology, March 2001, p. 2912-2920, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2912-2920.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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