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Journal of Virology, February 1999, p. 920-929, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutant with Increased Virulence and Reduced Spontaneous Reactivation

Guey-Chuen Perng,1 Susan M. Slanina,1 Ada Yukht,1 Barbara S. Drolet,1 William Keleher Jr.,1 Homayon Ghiasi,1,2 Anthony B. Nesburn,1,2 and Steven L. Wechsler1,2,*

Ophthalmology Research Laboratories, Cedars-Sinai Medical Center Burns & Allen Research Institute, Los Angeles, California 90048,1 and Department of Ophthalmology, UCLA School of Medicine, Los Angeles, California 900242

Received 18 September 1998/Accepted 22 October 1998

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) gene is essential for efficient spontaneous reactivation of HSV-1 from latency. We previously reported that insertion of the LAT promoter and just the first 1.5 kb of the 8.3-kb LAT gene into an ectopic location in the virus restored wild-type spontaneous reactivation to a LAT null mutant. This mutant, LAT3.3A (previously designated LAT1.5a), thus showed that the expression of just the first 1.5 kb of LAT is sufficient for wild-type spontaneous reactivation. We also showed that in the context of the entire LAT gene, deletion of LAT nucleotides 76 to 447 (LAT mutant dLAT371) had no effect on spontaneous reactivation or virulence. We report here on a LAT mutant designated LAT2.9A. This mutant is similar to LAT3.3A, except that the ectopic LAT insert contains the same 371-nucleotide deletion found in dLAT371. We found that LAT2.9A had a significantly reduced rate of spontaneous reactivation compared to marker-rescued and wild-type viruses. This was unexpected, since the combined results of dLAT371 and LAT3.3A predicted that spontaneous reactivation of LAT2.9A would be wild type. We also found that LAT2.9A was more virulent than wild-type or marker-rescued viruses after ocular infection of rabbits. This was unexpected, since LAT null mutants and LAT3.3A have wild-type virulence. These results suggest for the first time (i) that regions past the first 1.5 kb of LAT can compensate for deletions in the first 1.5kb of LAT and may therefore play a role in LAT dependent spontaneous reactivation and (ii) that regions of LAT affect viral virulence.

* Corresponding author. Mailing address: Ophthalmology Research Laboratories, Cedars-Sinai Medical Center Burns & Allen Research Institute, Davis Bldg., Rm. 5072, 8700 Beverly Blvd., Los Angeles, CA 90048. Phone: (310) 855-6457. Fax: (310) 652-8411. E-mail: Wechsler{at}CSMC.edu.

Journal of Virology, February 1999, p. 920-929, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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