Alpha-herpesvirinae subfamily members {herpes simplex virus type 1 (HSV-1), Pseudorables virus (PVR), and bovine herpesvirus 1 (BHV-1)} are significant viral pathogens of their respective hosts. Following initial infection and replication in mucosal epithelium, these viruses establish latency in glanglionic sensory neurons. Viral gene expression and replication occur in infected neurons, but many neurons survive. Patency protects these viruses from immune surveillance, maintains the viral genome in sensory neurons, and is pivotal for virus transmission. Stress, trauma, and immunosuppression, can induce reactivation, which leads to virus shedding and recurrent disease. Recurrent ocular shedding of HSV- 1 leads to corneal scarring that can progress to vision loss. Each of these viruses encodes a latency-associated transcript (LAT). LAT is the only abundant viral transcript expressed during latency and in small animal models HSV-1 LAT is important for reactivation. LAT is the only abundant viral transcript expressed during latency and in small animal models HSV-1 LAT is important for reactivation. HSV-1 and BHV-1 LAT gene products inhibit apoptosis (programmed cell death) in transiently transfected cells. An HSV-1 LAT null mutant induces extensive apoptosis in TG of infected apoptosis in TG of infected rabbits compared to HSV-1 strains that express LAT. Based on these results, we hypothesize that LAT promotes survival of infected neurons. Experiments in this proposal will: 1) determine if cellular of viral anti-apoptotic genes restore the reactivation deficiency of a HSV-1 LAT null mutant, 2) map the minimal LAT sequences that inhibit apoptosis, and 3) identify cellular genes that have altered expression as a result of LAT expression. Completion of theses studies will enhance our understanding of LAT's role in latency. This knowledge may be translated into innovative strategies into innovative strategies that interfere with latency and reactivation.

National Institute of Health (NIH)
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University of Nebraska Lincoln
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