Recurrent infections with herpes simplex virus (HSV) occur worldwide and may affect up to one-third of the world's population. In addition, recurrent hepatic keratitis is the leading causes of infectious corneal blindness in developed countries. An important concept in understanding the pathophysiology of recurrent hepatic disease is that the virus establishes latent infections in neurons. Primary sensory neurons are the classic reservoirs, but latent infections can also be established in autonomic, motor and a variety of CNS neurons. Periodic reactivation of the latent virus leads to recurrent disease. Although prophylactic antiviral therapy has proven effective in reducing the frequency and severity of recurrent non-ocular disease due to HSV, no therapy has proven effective in eliminating the virus from latently infected neurons. Development of such a therapy will undoubtably depend on an improved understanding of the cellular and molecular basis of latency and reactivation. The goal of our proposed research is to explore the role of host neurons in the regulations of transcription of the HSV genome in vivo as it pertains to the establishment of the latent state. Although work carried out during the last three years has revealed much about the host cell regulation of infection with HSV in transient assays and cell culture lines, very little of this has been validated in vivo. Through the use of genetically engineered viruses, nucleic acid probes and multiple labeling techniques we hope to being to study the role of the host factors in transcriptional regulation of the HSV genome in vivo. We will specifically investigate, on a cell by cell basis, viral gene expression in acutely infected ocular primary sensory neurons in order to study the ability of neuronal sub-populations to differentially regulated the outcome of infection with HSV. In addition we will attempt to correlate the expression of specific host transcriptional regulatory proteins. (Oct-1, Oct-2, trkA, gamma interferon), known to influence viral gene vectors we will attempt to over-express these same 'suspect' host regulatory proteins in acutely infected neurons in order to determine whether these factors are capable of influencing the outcome of viral gene expression in vivo.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Experimental Virology Study Section (EVR)
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University of California San Francisco
Other Domestic Higher Education
San Francisco
United States
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