TRIGEMINAL NEUROBIOLOGY--REACTIVATION OF LATENT HSV-1

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Herpes simplex virus (HSV) infections consist of several distinct stages; namely a primary infection, a latent infection and a reactivation of latent virus producing recurrent disease. In HSV infections of the mouth (herpes labialis), the trigeminal ganglion serves as the site of latent infection. Since a large portion of the population is estimated to have latent HSV infections and since recurrent infections probably represent the largest reservoir of HSV, efforts to control viral reactivation and therefore recurrent infections are extremely important in controlling the spread of the virus in the population. The exact mechanism(s) of HSV latency and reactivation including the roles of the immune, nervous and endocrine systems are largely unknown. Studies designed to unravel the interactions and roles of these different systems in viral reactivation from within the trigeminal ganglia are required before effective intervention can be designed. The single most important tool needed to study HSV reactivation is a good animal model, which unfortunately, does not currently exist. The primary goal of this research proposal is to establish an animal model system for the reactivation of latent HSV-1 from the trigeminal ganglia of mice. Using a well established mouse corneal model for HSV latency, viral reactivation will be achieved using a variety of stressors including infection with mouse hepatitis virus or salmonella typhimurium; use of the immuno-suppressive drugs cyclophosphamide and cyclosporin A; general anesthesia; and exposure to sub-erythemal doses of ultra-violet irradiation. Viral reactivation will be detected by monitoring HSV- specific immunoglobulins, cytotoxic T-cell activity, isolation of infectious virus and the presence of HSV-specific proteins in mouse tissues. Using this model system, additional studies will be performed to analyze the role of immune T cells, and the cytokines interleukin-1 (IL1), IL2, IL6, tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), and transformed growth factor beta (TGFbeta) in the reactivation of latent HSV-1 virus.