Corneal infectious diseases have put at risk the vision of more than 250 million individuals and have blinded over 6 million worldwide. In the United States, herpetic eye disease is the most common infectious agent of corneal blindness, causing permanent structural damage to the cornea. This is the result of the ability of herpes simplex virus (HSV) to establish latent infections that can reactivate to cause recurrent herpetic keratitis. The rate of recurrence in the eye has a major impact on the degree of corneal damage and the eventual outcome for the patient. Because the number of neurons in which latency is established directly correlates with the frequency of HSV reactivation, those factors regulating the establishment of latency also influence the outcome of ocular infections. We have made significant progress toward our past objective of determining the molecular mechanisms by which LAT prevents the death of neurons and promotes the establishment of latency. We have recently discovered that transcription from the LAT locus is the first viral transcriptional activity that occurs upon infection of sensory neurons, detectable as early as 20h pi and at least 10 hr before any other viral transcription. Thus entry into latency is the default pathway in neurons infected from the periphery in vivo. In the absence of LAT, ~25% more neurons exit the default latent program and enter the lytic cycle and this is detectable as early as 48h pi. In addition, we have determined that expression of a small portion of LAT sequences as an artificial unstable intron results in the full restoration of LAT null mutants'ability to inhibit exit from the latent program and thus establish wild type numbers of latent infections. Our long term goal is to delineate the molecular mechanisms of HSV pathogenesis in vivo so that effective therapeutic strategies can be developed to treat and/or prevent infection. Our objective is to define precisely the biochemical mechanisms of LAT function and to exploit these mechanisms to prevent eye disease. Our central hypothesis is LAT functions to inhibit the exit from the latent program by generating inhibitory RNA molecules that target one or more of the viral transcriptional activators. Specifically we will (1) Determine how the 1.4 kb LAT related Unstable Artificial Intron (LAT-UAI) functions to enhance the establishment of latency;(2) Determine the biochemical basis for the function of LAT-UAI;and (3) Determine how alterations in the stability of the LAT introns regulate the establishment of latent infections.The long-term goal of the proposed research is to define how herpes simplex virus causes recurrent disease that is a leading cause of corneal blindness. We have discovered a biochemical mechanism encoded by the virus that can block reactivation from the latent state and prevent recurrent disease. We plan to determine how this mechanism operates, and this knowledge will lead directly to improved vaccine design and preventative therapies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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University of Cincinnati
Schools of Medicine
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Thompson, Richard L; Sawtell, Nancy M (2011) The herpes simplex virus type 1 latency associated transcript locus is required for the maintenance of reactivation competent latent infections. J Neurovirol 17:552-8
Sawtell, Nancy M; Triezenberg, Steven J; Thompson, Richard L (2011) VP16 serine 375 is a critical determinant of herpes simplex virus exit from latency in vivo. J Neurovirol 17:546-51
Thompson, Richard L; Sawtell, Nancy M (2010) Therapeutic implications of new insights into the critical role of VP16 in initiating the earliest stages of HSV reactivation from latency. Future Med Chem 2:1099-105
Thompson, Richard L; Preston, Chris M; Sawtell, Nancy M (2009) De novo synthesis of VP16 coordinates the exit from HSV latency in vivo. PLoS Pathog 5:e1000352
Sawtell, N M; Thompson, R L; Haas, R L (2006) Herpes simplex virus DNA synthesis is not a decisive regulatory event in the initiation of lytic viral protein expression in neurons in vivo during primary infection or reactivation from latency. J Virol 80:38-50
Thompson, R L; Sawtell, N M (2006) Evidence that the herpes simplex virus type 1 ICP0 protein does not initiate reactivation from latency in vivo. J Virol 80:10919-30
Sawtell, N M; Thompson, R L (2004) Comparison of herpes simplex virus reactivation in ganglia in vivo and in explants demonstrates quantitative and qualitative differences. J Virol 78:7784-94
Sawtell, N M (2003) Quantitative analysis of herpes simplex virus reactivation in vivo demonstrates that reactivation in the nervous system is not inhibited at early times postinoculation. J Virol 77:4127-38
Foster, William J; Fuller, Christine E; Perry, Arie et al. (2003) Status of the NF1 tumor suppressor locus in uveal melanoma. Arch Ophthalmol 121:1311-5
Thompson, R L; Shieh, May T; Sawtell, N M (2003) Analysis of herpes simplex virus ICP0 promoter function in sensory neurons during acute infection, establishment of latency, and reactivation in vivo. J Virol 77:12319-30

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