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.
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