Intravaginal inoculation of guinea pigs with herpes simplex virus (HSV) produces a self-limited genital infection resulting in the establishment of a persistent infection of neural (e.g. dorsal root ganglia) and extraneural (e.g. genital skin uterine cervix) tissues. Guinea pigs also exhibit spontaneous subclinical as well as symptomatic recurrent infection and alteration in cervicovaginal cytology. These aspects of HSV infection may be quantitatively assessed by clinical illness scores, virus plaque titration, explant cocultivation, HSV DNA hybridization, and exfoliative cytologic examination. Utilizing the guinea pig model of genital HSV disease we propose to evaluate the conservation of persistent virus and viral DNA over time and its relationship(s) to primary and recurrent infection. We will determine the pattern of persistent and recurrent infection produced by different genotypic virus strains including intertypic recombinant mutants in order to define viral factors important in the control of viral persistence and the expression of recurrent disease. We will exploit manipulations of the model known to produce alterations in the pattern of primary or recurrent disease in order to explore the role of host factors, such as animal strain or maturity, in the establishment and maintenance of the persistent state. We will determine the humoral, interferon and cell-mediated immune responses associated with primary and recurrent infection and correlate host immune responses with the natural history of persistent infection in order to further delineate those host responses that are most important in limiting persistent infection and altering the expression of recurrent disease. By utilizing in situ hybridization techniques we will define the cell type harboring persistent virus in extraneural tissues and by pharmacologic manipulations we will determine whether virus persistent in extraneural tissues exists in a state similar to virus latent in sensory neuroganglia. Additionally, we will employ DNA hybridization methods and exfoliative cytologic techniques to define the natural history of HSV persistence in the uterine cervix. The long term goal of this proposal is to expand our understanding of the pathophysiology of persistent infection, thus ultimately providing new approaches to control of disease resulting from HSV persistence.
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