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Journal of Virology, April 2000, p. 3613-3622, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Evidence for a Bidirectional Element Located Downstream from the Herpes Simplex Virus Type 1 Latency-Associated Promoter That Increases Its Activity during Latency

Herve Berthomme,1,dagger James Lokensgard,1 Li Yang,2 Todd Margolis,2 and Lawrence T. Feldman1,*

Department of Microbiology and Immunology, UCLA School of Medicine, Los Angeles, California 90095,1 and F. I. Proctor Foundation and Department of Ophthalmology, University of California at San Francisco, San Francisco, California 941432

Received 16 November 1999/Accepted 12 January 2000

Herpes simplex virus type 1 (HSV-1) latent infection in vivo is characterized by the constitutive expression of the latency-associated transcripts (LAT), which originate from the LAT promoter (LAP). In an attempt to determine the functional parts of LAP, we previously demonstrated that viruses harboring a DNA fragment 3' of the LAT promoter itself were able to maintain detectable promoter expression throughout latency whereas viruses not containing this element could not (J. R. Lokensgard, H. Berthomme, and L. T. Feldman, J. Virol. 71:6714-6719, 1997). This element was therefore called a long-term expression element (LTE). To further study the role of the LTE, we constructed plasmids containing a DNA fragment encompassing the LTE inserted into a synthetic intron between the reporter lacZ gene and either the LAT or the HSV-1 thymidine kinase promoter. Transient-expression experiments with both neuronal and nonneuronal cell lines showed that the LTE locus has an enhancer activity that does not activate the cytomegalovirus enhancer but does activate the promoters such as the LAT promoter and the thymidine kinase promoter. The enhancement of these two promoters occurs in both neuronal and nonneuronal cell lines. Recombinant viruses containing enhancer constructs were constructed, and these demonstrated that the enhancer functioned when present in the context of the viral DNA, both for in vitro infections of cells in culture and for in vivo infections of neurons in mouse dorsal root ganglia. In the infections of mouse dorsal root ganglia, there was a very high level of promoter activity in neurons infected with viruses bearing the LAT promoter-enhancer, but this decreased after the first 2 or 3 weeks. By 18 days postinfection, neurons harboring latent virus without the enhancer showed no beta -galactosidase (beta -gal) staining whereas those harboring latent virus containing the enhancer continued to show beta -gal staining for long periods, extending to at least 6 months postinfection, the longest time examined.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, 43-169CHS, UCLA School of Medicine, Los Angeles, CA 90095-1405. Phone: (310) 206-1014. Fax: (310) 206-3865. E-mail: lfeldman{at}microimmun.medsch.ucla.edu.

dagger Present address: Centre de Genetique Moleculaire et Cellulaire, UMR5534 CNRS, Université Claude Bernard Lyon 1, Villeurbanne Cedex, France.

Journal of Virology, April 2000, p. 3613-3622, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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