Although encephalitis of human adults can be caused by several infectious agents, herpes simplex virus type 1 (HSV-1) is considered a leading cause of sporadic fatal encephalitis in the United States. In humans, HSV-1 encephalitis is often characterized by necrotizing inflammatory lesions in the temporal lobes, but interestingly, recent studies indicate that HSV-1 can also induce severe behavioral or memory disturbances in the absence of overt signs of brain infection. recent studies showing that HSV-1 can establish latency within the human brain have validated findings from animal models that suggested viral invasion via the olfactory pathway may be fundamental to producing the sterotypic encephalitic lesions associated with acute or reactivated forms of this disease. Evidence has been obtained from several animal models that implicates a specific viral glycoprotein as a cause of seizures, and I n the ability of HSV-1 to spread to the central nervous system (CNS) centers involved with olfaction and memory and learning, including the olfactory bulb, cortex, the entorhinal cortex, amygdala, and hippocampus. In this proposal, very specific types of intratypic recombinant viruses will be utilized as tools to examine th3e domains of this glycoprotein as they relate to the ability of HSV-1 to spread to specific CNS sensory centers, to induce limbic seizures, and to induce learning disabilities after intranasal infection. Experimentally infected animals will be assessed for the production of clinical signs of infection including seizure development, for electroencephalographic evidence of encephalitis, and for the appearance of viral-specific products within the CNS olfactory system and the sensory areas of the CNS involved with memory and learning by histopathological and virological techniques. To correlate infection of CNS areas involved in learning, animals will be tested for their ability to learn a complex allocentric-spatial task after intranasal infection. these studies are fundamental to our understanding of the viral factors that contribute to the manifestations of CNS disease seen with strains of HSV and to the development of safe and effective HSV vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001706-10
Application #
6379310
Study Section
Neurology A Study Section (NEUA)
Program Officer
Davis, Barry
Project Start
1992-07-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2003-06-30
Support Year
10
Fiscal Year
2001
Total Cost
$274,764
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Kienzle, T E; Chen, T M; Mrak, R E et al. (2001) A novel, cell-specific attenuation of a herpes simplex virus type 1 infection in vivo. Acta Neuropathol (Berl) 101:341-50
Neufeld, M V; Steinemann, T L; Merin, L M et al. (1999) Identification of a herpes simplex virus-induced dendrite in an eye-bank donor cornea. Cornea 18:489-92
Ling, J Y; Kienzle, T E; Chen, T M et al. (1997) Comparative analyses of the latency-associated transcript promoters from herpes simplex virus type 1 strains H129, +GC and KOS-63. Virus Res 50:95-106
Beers, D R; Henkel, J S; Kesner, R P et al. (1995) Spatial recognition memory deficits without notable CNS pathology in rats following herpes simplex encephalitis. J Neurol Sci 131:119-27
Chodosh, J; Miller, D; Stroop, W G et al. (1995) Adenovirus epithelial keratitis. Cornea 14:167-74
Kienzle, T E; Henkel, J S; Ling, J Y et al. (1995) Cloning and restriction endonuclease mapping of herpes simplex virus type-1 strains H129 and +GC. Arch Virol 140:1663-75
Stroop, W G; Banks, M C (1994) Herpes simplex virus type 1 strain KOS-63 does not cause acute or recurrent ocular disease and does not reactivate ganglionic latency in vivo. Acta Neuropathol 87:14-22
Chodosh, J; Dix, R D; Howell, R C et al. (1994) Staining characteristics and antiviral activity of sulforhodamine B and lissamine green B. Invest Ophthalmol Vis Sci 35:1046-58
Stroop, W G; Banks, M C; Qavi, H et al. (1994) A thymidine kinase deficient HSV-2 strain causes acute keratitis and establishes trigeminal ganglionic latency, but poorly reactivates in vivo. J Med Virol 43:297-309
Beers, D R; Henkel, J S; Schaefer, D C et al. (1993) Neuropathology of herpes simplex virus encephalitis in a rat seizure model. J Neuropathol Exp Neurol 52:241-52

Showing the most recent 10 out of 11 publications