The long-term goals of this program are an understanding of central nervous system (CNS) demyelinating disease. To this end, this program contains a multidisciplinary approach to defining mechanisms of myelin loss using a well defined rnurine model of demyelination induced by the neurotropic JHM strain (MHV-4) of mouse hepatitis virus (JHMV). This model provides a means to understand the interactions between a pathogen and its natural host that result in demyelination during acute and persistent CNS infection. Although the host response is competent to control infectious virus, a persistent infection without detectable infectious virus is associated with chronic ongoing myelin loss, which has numerous similarities to multiple sclerosis, the most prevalent human demyelinating disease. This program is unique, offering a stable core of investigators addressing fundamental questions of viral persistence and immune responses, both as protective mechanisms and as inducers of demyelination. Funding is requested for continuation of Project 12 (Norman Marten), Project 2 (Stephen Stohlman) and Project 10 (Cornelia Bergmann) and for addition of a new project directed by Thomas Lane. Project 12 focuses on the initial events in CNS inflammation including the role of innate cytokines and neutrophils in shaping both the innate and adaptive CNS immune response, and an exciting new approach to understanding how T cells traffic through the CNS parenchyma. Project 2 continues an examination of the role of distinct CD8+ T cell effectors mechanisms in controlling virus replication in oligodendroglia and astrocytes, the mechanisms used by oligodendroglia to resist perforin mediated cytolysis and the negative co-receptors which limit T cell effector function leading to persistent infection. Project 10 analyzes the role of MHC and costimulatory molecule expression by individual CNS cell types in modulating both acute and chronic demyelination. Project 13 focuses on the role(s) of the chemokine IP-10. Specifically, molecular regulation of IP-10 expression in JHMV infected astrocytes will be examined. In addition, the cellular basis for IP-10 mediated attraction of both T cells and macrophages into the CNS is determined. Data obtained from these projects will add to the basic understanding of viral pathogenesis within the CNS and importantly, provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination with the cellular and soluble mediators of the host immune response.