Primary varicella zoster virus (VZV)infection produces chickenpox (varicella), after which virus becomes latent in ganglia reactivates to produce zoster (shingles). Neurological complications of zoster are increased in the aging population whose cell-mediated immunity to VZV is reduced. During varicella, virus enters ganglia by hematogenous spread or by retrograde axonal transport from skin infected by tonsillar memory CD4+ T cells. VZV-specific T cells are not essential to maintain latency in ganglia. Virus latency and reactivation is probably regulated by an innate immune response involving cytokines or chemokines. We developed an experimental animal model that parallels VZV infections in humans. Natural infection of primates with simian varicella virus (SW) leads to ganglionic latency and reactivation after irradiation and treatment with immunosuppressive drugs. Reactivation of SW is accompanied by changes in cytokine levels and by appearance of T cell clusters adjacent to neurons in ganglia with reactivated virus. These data provide the rationale for our hypothesis that both immune cells and non-immune cells as well as cytokines released by these cells upon their interaction with neurons are important determinants of the course of primary varicella, latency and reactivation. To determine the route of SW infection of skin and sensory ganglia, we will identify the host cell types and their role in the transport and establishment of SW infection in skin and in ganglia after primary infection (Aim 1). Because, SW latency and reactivation in ganglia are more likely regulated by an innate immune response involving cytokines, we will comparethe cytokine expression during latency and reactivation in monkey ganglia (Aim 2). To identify the SW-specific T cell response in ganglia during reactivation, we will identify the phenotype and specificity of T cells infiltrating ganglia during SW reactivation (Aim 3). A comprehensive knowledge of the cell types and immunological factors that influence the transport of SW from the site of primary infection to skin and sensory ganglia along with an understanding of the local SVV-specific T cell response in ganglia during latency and reactivation will identify potential targets for prevention of zoster in humans. The latter is of particular importance in the rapidly increasing elderly and immunocompromised populations, who often develop chronic and sometimes fatal neurological disease produced by VZV reactivation.
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