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Based on the seroprevalance rates, between 150 and 200 million Americans are latently infected with herpes simplex virus type l (HSV-1) of which 20% will undergo recurrent reactivation. Most of the morbidity associated with HSV-l infection is a result of the repeated activation of latent virus that occurs throughout the lifetime of the host. Sensory neurons (dorsal root or trigeminal ganglia [TG]) serve as the reservoir for latent HSV-l. The activation of the hypothalamic pituitary adrenal axis and the sympathetic/parasympathetic nervous system are thought to be involved in inducing reactivation of latent HSV-l. By augmenting or eliciting an immune response early during the infection, it is possible to antagonize viral replication, reduce the occurrence of viral-mediated encephalitis, and antagonize the establishment of HSV-l latency and the incidence of reactivation. This laboratory has begun to study the role of an early immune response on the outcome of acute ocular HSV-l infection focusing on innate immunity. A metabolite of the endogenous hormone dehydroepiandrosterone, androstenediol (AED) has been found to protect mice from HSV-l infection by increasing interferon-alpha levels early during the course of infection. Preliminary data also suggest AED enhances selective chemokine and cytokine expression in the sensory ganglia and augments natural killer activity following subcutaneous administration of the metabolite. However, the expression of the cytokines/chemokines, the potential involvement of natural killer cells and neurotransmitter levels within the sensory ganglia of infected mice treated with AED relative to viral gene expression, replication, and reactivation from a latent state has not been established. The goal of the specific aims is to determine the relationship between viral gene expression and the immune response focusing on early events elicited by AED treatment within the confines of the sensory ganglia (i.e., TG) and eyes. Specifically, these studies will: l) characterize the infiltrating immune cells within the TG of mice treated with and without AED treatment, 2) establish the monoanimine profile in the eye, TG, and cerebellum of mice undergoing acute HSV-l infection treated with or without AED, 3) compare the expression of viral immediate early, early, and late genes in comparison to cytokine/chemokine transcripts and protein in the eye and TG of mice over the course of the acute infection (1-7 days post infection), and 4) characterize the reactivation kinetics of latent HSV-l in mice treated with or without AED. Since dehydroepiandrosterone and by inference AED decreases during the aging process, it is anticipated that the results of this project will contribute to our knowledge of susceptibility to infectious pathogens in the elderly.
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