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Title: Expression of the first 811 nucleotides of the herpes simplex virus type 1 latency-associated transcript (LAT) partially restores wild-type spontaneous reactivation to a LAT-null mutant

Author
item Drolet, Barbara
item PERNG, G. - UNIV OF CALIF-IRVINE
item VILLOSIS, R. - CEDARS-SINAI MED CENTER
item SLANINA, S. - CEDARS-SINAI MED CENTER
item NESBURN, A. - CEDARS-SINAI MED CENTER
item WECHSLER, S. - UNIV OF CALIF-IRVINE

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/27/1998
Publication Date: N/A
Citation: Drolet, B.S., G.C. Perng, R.J. Villosis, S.M. Slanina, A.B. Nesburn, S.L. Wechsler. 1999. Expression of the first 811 nucleotides of the herpes simplex virus type 1 latency-associated transcript (LAT) partially restores wild-type spontaneous reactivation to a LAT-null mutant. Virology 253(1):96-106.

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 mutant was tested for its ability to cause recurrent infections, with the optimal goal of determining the genetic region responsible for spontaneous reactivation. Results of this study showed that the 811 nucleotide (nt) region being investigated was important in the ability of the virus to spontaneously reactivate in the rabbit eye model. However, the 811 nt region, alone, was only able to produce half the amount of spontaneous reactivation as the native (wild type) virus. This study suggests that either an adjacent gene sequence or a sequence further downstream is important in producing wild type levels of spontaneous reactivation.

Technical Abstract: The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) gene is required for efficient spontaneous reactivation in the rabbit ocular model. We recently showed that insertion of 1.8 kb of the LAT promoter and the first 1.5 kb of the 8.3 kb primary LAT transcript into a novel, ectopic location in the virus unique long (UL) region restored wild-type spontaneous reactivation to a LAT-null mutant. To further map the LAT spontaneous reactivation function within the first 1.5 kb of LAT, we rescued the same LAT-null mutant by inserting 1.8 kb of the LAT promoter and just the first 811 nucleotides of LAT into the same location in the UL. In a series of three experiments, the resulting virus, designated LAT2.6A, had a spontaneous reactivation rate that was midway between the original LAT-null mutant and wild-type virus. Thus expression of the first 811 LAT nucleotides produced a spontaneous reactivation rate that was significantly higher than that of the LAT-null mutant but significantly less than that of wild type. This suggests that part, but not all, of the LAT function involved in efficient spontaneous reactivation is located within the first 811 nucleotides of the primary 8.3 kb LAT.