Recurrent herpes simplex virus type 1 (HSV-1) ocular infections are the leading infectious cause of blindness in industrialized nations. Although HSV-1 can reactivate spontaneously, stress and trauma (e.g., hypo- and hyperthermia, ultraviolet light irradiation, and ocular surgery) also reactivate latent HSV-1. A high frequency of recurrent ocular infection typically leads to corneal scarring, loss of visual acuity, and possibly blindness. The goal of this proposal is to determine key genetic elements that lead to stress-related HSV-1 reactivation from latency and to differentiate these from genetic elements responsible for spontaneously occurring reactivation. Adrenergically-induced and spontaneous reactivation of virus from neural tissue has been mapped to a region of the HSV-1 genome which codes for the latency-associated transcript (LAT), the only viral transcript abundantly produced during latency. Certain clinical strains of HSV-1 can be distinguished by their reactivation frequency profiles: strain 17Syn+ displays both high spontaneous/high induced frequencies of reactivation, CGA-3 displays low spontaneous/low induced frequencies of reactivation, and Rodanus displays high spontaneous/low induced frequencies of reactivation. While 17Syn+ has been completely sequenced, no sequence information has been obtained from either CGA-3 or Rodanus. Our current research aims are to 1) sequence the LAT promoter regions of both CGA-3 and Rodanus and analyze them for the presence of transcription factor binding sites; 2) identify DNA-binding proteins that may govern stress-induced transcription of the LAT gene; and 3) construct and assay a chimeric mutant containing the Rodanus LAT region on a background of 17Syn+. The identification of these transcriptional activating sites is a necessary foundation for the elucidation of the HSV reactivation mechanism and ultimately for therapeutic strategies to prevent reactivation.

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Texas A&M University-Kingsville
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