Recurrent herpes simplex virus (HSV) infections afflict millions of Americans. This application proposes to study the pathophysiology of recurrent HSV infection by using an experimental model. Intravaginal HSV inoculation of guinea pigs produces a self-limited genital infection resulting in the establishment of a persistent infection in neural and extraneural tissues. Like humans, guinea pigs exhibit spontaneous subclinical as well as symptomatic recurrent infections and induced recurrent infections follow exposure to ultraviolet (UV) radiation. This unique model of human disease will be used to explore the host and viral factors which are important determinants of latent and recurrent infection. Quantification of the concentration of latent HSV genome in ganglia by a polymerase chain reaction DNA amplification method will be used to investigate the natural history of latent infection. In situ hybridization will be used to examine HSV-1 and HSV-2 transcription in persistently infected tissues. The extent of transcription at neural and extraneural sites will be correlated with the ability of the virus to produce recurrent disease. The differential ability of HSV-1 and HSV-2 to produce recurrent genital infection will be explored using intertypic HSV-1, X HSV-2 mutants. Molecular analyses of these mutants will define the regions of the HSV-2 genome responsible for recurrent genital herpes. Studies of neuron-virus interaction will provide new information regarding the cellular events involved in HSV pathogenesis. Sensory neurons in vivo will be selectively perturbed by pharmacological means to determine how alterations in neuronal function affects latency and recurrent disease. Studies of UV radiation-induced recurrent infection will explore how trigger factors produce recurrent herpes. In situ hybridization will be used to study the effect of UV irradiation on viral transcription in latently infected tissues. Specific immune augmentation studies will explore the relative importance of humoral and cell mediated immune responses, while, pharmacological studies will examine the role of prostaglandins in induced recurrent herpes. The long term goal of this proposal is to expand our understanding of the pathophysiology of latent and recurrent HSV infection, thus ultimately providing new approaches to control an exceedingly common public health problem.
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