This unique proposal will test the hypothesis that neuronal-specific regulatory mechanisms control latency and reactivation of herpes simplex virus (HSV)-1 and 2, and that the regulation of HSV latency and reactivation requires interaction with a cascade of cellular signaling pathways mediated by nerve growth factor (NGF). The rationale for this hypothesis is that reactivation of HSV from latency is dependent on neuronal signal pathways mediated by NGF, cAMP and protein kinase C (PKC). First the efficiency of establishment of latency of HSV-1 and 2 will be determined: by quantitation of HSV latency-associated transcripts (LATs), by determining the abundance of neurons containing LATs. and by determining the neuronal subtype, if any, specific for latency. Second, since the biology of HSV-1 and HSV-2 is different in humans and may reflect basic differences in the viruses' interactions with neurons, the ability of both HSV-1 and HSV-2 to reactivate to specific neuronal signal pathways will be compared. Reactivation of both viruses from latency will be examined in response to the following signals: NGF, cAMP and PKC. Third, the mechanism(s) involved in NGF-mediated signaling responsible for maintaining HSV latency will be determined. This will be done by investigating the distal step of NGF signaling involving: Ras and MAP kinases, protein kinase N, and the interaction of these pathways with cAMP and PKC-mediated signaling. Taken together, these studies will increase our understanding of two herpesviruses which cause the most common serious encephalitis and most common recurrent venereal disease, respectively, in the United States. As a result of these studies, the understanding of herpes simplex virus latency will be increased, and this information may lead to novel approaches for the treatment of diseases caused by HSV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001741-04
Application #
2416232
Study Section
NST-2 Subcommittee (NST)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1994-07-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Smith, R L; Morroni, J; Wilcox, C L (2001) Lack of effect of treatment with penciclovir or acyclovir on the establishment of latent HSV-1 in primary sensory neurons in culture. Antiviral Res 52:19-24
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Smith, R L; Clayton, G H; Wilcox, C L et al. (1995) Differential expression of an inwardly rectifying chloride conductance in rat brain neurons: a potential mechanism for cell-specific modulation of postsynaptic inhibition. J Neurosci 15:4057-67