Spread of herpes simplex virus type 1 in the central nervous system during experimentally reactivated encephalitis

Abstract

Because many of the features of reactivated herpes simplex virus type 1 (HSV-1) central nervous sytems (CNS) infections in vivo are incompletely understood, we used an animal model to study the development of the morphological, ultrastructural, radiological and immunological changes which occurred during acute and experimentally reactivated diseases. Rabbits were intranasally inoculated with HSV-1, and their latent trigeminal ganglionic and CNS infections were reactivated by intravenous injection of cyclophosphamide and dexamethasone. Technetium brain scans were performed to localize areas of blood-brain barrier breakdown, and cerebrospinal fluid (CSF) was analysed for IgG content by radial immunodiffusion assays. Nervous system tissues were studied by in situ hybridization and by immunofluorescent, light and electron microscopic techniques. Diffuse uptake of technetium was observed as HSV-1 spread transsynaptically into the brain during the acute phase of infection, and viral antigens and nucleic acids were detected in both the CNS olfactory and trigeminal systems. During latency, viral RNA was detected in the nuclei of neurons within the CNS olfactory cerebral and entorhinal cortices, indicating that HSV-1 became latent within the same CNS structures that were involved during the acute phase of infection. Following drug-induced reactivation, the brain scans revealed a more focal breakdown of the blood-brain barrier, and both neurons and neuronal processes in the entorhinal and olfactory cortices contained viral nucleic acids which correlated with the ultrastructural presence of HSV-1 virions. During the reactivated phase of infection a marked increase in the CSF IgG index occurred without an increase in the CSF: serum albumen ratio indicating a prompt intrathecal response in infected rabbits as compared to controls. To some extent, the CSF IgG index reflected the degree of histopathological damage.