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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010008-02
Application #
2163703
Study Section
Experimental Virology Study Section (EVR)
Project Start
1993-12-01
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Other Domestic Higher Education
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Leigh, Julie F; Acharya, Nisha; Cevallos, Vicky et al. (2008) Does asymptomatic shedding of herpes simplex virus on the ocular surface lead to false-positive diagnostic PCR results? Br J Ophthalmol 92:435-6
Margolis, Todd P; Elfman, Fred L; Leib, David et al. (2007) Spontaneous reactivation of herpes simplex virus type 1 in latently infected murine sensory ganglia. J Virol 81:11069-74
Margolis, Todd P; Imai, Yumi; Yang, Li et al. (2007) Herpes simplex virus type 2 (HSV-2) establishes latent infection in a different population of ganglionic neurons than HSV-1: role of latency-associated transcripts. J Virol 81:1872-8
Seitzman, Gerami D; Cevallos, Vicky; Margolis, Todd P (2006) Rose bengal and lissamine green inhibit detection of herpes simplex virus by PCR. Am J Ophthalmol 141:756-8
Margolis, Todd P; Whitcher, John P (2006) Fusarium--A new culprit in the contact lens case. JAMA 296:985-7
Prabriputaloong, Tisha; Margolis, Todd P; Lietman, Thomas M et al. (2006) Atopic disease and herpes simplex eye disease: a population-based case-control study. Am J Ophthalmol 142:745-9
Kim, E C; Margolis, T P (2006) Hypertensive iridocyclitis. Br J Ophthalmol 90:812-3
Acharya, Nisha; Lietman, Thomas; Cevallos, Vicki et al. (2006) Correlation between clinical suspicion and polymerase chain reaction verification of infectious vitritis. Am J Ophthalmol 141:584-5

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