Invasion of the brain by herpes simplex virus type 1 (HSV-1) produces a necrotizing encephalitis in adults which is acconpanied by severe mortality and morbidity. Acute disease often leads to changes in the cellular and protein content of the cerebrospinal fluid (CSF) which in part reflect a localized immune response within the central nervous system (CNS). The normal evolution of localized virus-specific antibody production and its role in the pathogenesis of herpes simplex encephalitis (HSE) it recovery from this devastating disease remains poorly understood. To this end, experiments will be performed to define in detail the pattern of antibody changes within CSF during periods of active virus replication, virus clearance, and recovery from acute disease. First, the temporal development of immunoglobulins IgM, IgG, and IgA within CSF will lbe assessed using the rabbit model of HSE. Results will be compared with immunoglobulin levels found in matched serum samples. Second, matched CSF and serum obtained from infected rabbits at various stages of the disease will be examined and compared for the pattern of IgG synthesis to individual virus-induced proteins and glycoproteins. Third, the pattern of antibody changes within the CSF of encephalitic rabbit administered either adenine arabinoside (Ara-A) or acycloguanosine (acyclovir; ACV) will be assessed to define with some precision the potential effect of antivirals on localized antibody synthesis during HSE. Fourth, identical quantitative antibody studies will be performed using acute and convalescent CSF and serum recovered from patients with biopsy-proven HSE. Techniques used during these studies include enzyme-linked immunosorbent assays, SDS-polyactrylamide slab gel electrophoresis, immunoprecipitation and electroblot (Western blot) procedures, and various virological assays. Information derived from the proposed project will provide a better understanding of the localized immune responses within CNS tissue during the progression of HSE and may lead to the development of improved diagnostic and therapeutic approaches for the control of this devastating encephalitis illness in man.
