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Title: A herpes simplex virus type 1 latency-associated transcript mutant with increased virulence and reduced spontaneous reactivation

Author
item PERNG, G. - UNIV OF CALIF-IRVINE
item SLANINA, S. - CEDARS-SINAI MED CENTER
item YUKHT, A. - CEDARS-SINAI MED CENTER
item Drolet, Barbara
item KELEHER, JR., W. - CEDARS-SINAI MED CENTER
item GHIASI, H. - CEDARS-SINAI MED CENTER
item NESBURN, A. - CEDARS-SINAI MED CENTER
item WECHSLER, S. - UNIV OF CALIF-IRVINE

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/1998
Publication Date: N/A
Citation: Perng, G.C., S.M. Slanina, A. Yukht, B.S. Drolet, W. Keleher, Jr., H. Ghiasi, A.B. Nesburn, S.L. Wechsler. 1999. A herpes simplex virus type 1 latency-associated transcript mutant with increased virulence and reduced spontaneous reactivation. Journal of Virology 73(2):920-929.

Interpretive Summary: Herpes simplex virus Type 1 (HSV-1) is the causative agent for an infectious, chronic, recurrent disease of the eye called herpetic keratitis. Herpetic keratitis is the most common cause of infectious blindness in the United States. The rabbit ocular model is used to determine which viral genes are necessary to establish infection in the eye and result in the subsequent latency stage of the virus in the nerves of the eye. It is from these nerves that recurrent infections arise through a process called "spontaneous reactivation". In this study, a genetic viral mutant was tested for its ability to spontaneously reactivate in the rabbit eye model. Up until this study the ability of HSV-1 to reactivate was thought to lie within a specific region of one gene. This study showed, for the first time, that a region further downstream in the gene was also important for this function. This study also showed, that this gene had an affect on the virus' ability to cause disease, a function not previously assigned to this gene.

Technical Abstract: 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 LAT gene into an ectopic location in the virus restored wild-type spontaneous reactivationto 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 76-447 (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 LAT 3.3A, 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 1.5 kb of LAT and may therefore play a role in LAT dependent spontaneous reactivation and (ii) that regions of LAT affect viral virulence.