Borna disease virus (BDV) replicates only in the nervous system and produces a persistent, productive infection. This molecularly uncharacterized agent infects a wide range of species, from chimpanzees to chickens, and is identified by a unique virus associated antigen. A similar virus has been identified in patients with neurological and psychiatric illnesses (eg. schizophrenia, manic depressive disorders). Disease expression in Borna disease ranges from social behavioral abnormalities in tupiais to fatal encephalomyelitis in its natural hosts, horses and sheep. BDV infection in the rat is one of only a few models of chronic viral encephalitis. In rats, the first signs of Borna disease are aggression and ataxia (acute disease), followed by listlessness and hypoactivity (chronic disease). The surviving animals remain in the chronic disease state for life. In acute disease there is a transient, necrotizing encephalitis and an associated loss of infected neurons. Subsequently, resolution of inflammation occurs despite increasing numbers of BDV-infected glial cells (eg. astrocytes). Neonatally inoculated rats become persistently infected but develop no signs of disease or inflammation (persistent, tolerant infection or PTI). Preliminary data reveal that MHC I and II expression also persists in chronic disease, even after the resolution of inflammation. This proposal will investigate 1. The mechanisms of destruction of infected neurons and sparing of infected glial cells, and 2. The relationship of these events to the decline in inflammation during chronic Borna disease. 1. MHC I and II expression in the BDV-infected nervous system will be described. Individual neural cells expressing MHC (eg. infected neurons, astrocytes, and Schwann cells) will be identified using double label immunohistochemistry and one micron thick serial sections. Tissue sections from BDV-infected rats with encephalitis, post-encephalitis, and no encephalitis (PTI) will be stained with cell, BDV antigen and MHC specific antibodies 2. Infected astrocytes from rats in each stage of disease will be cultured and examined in vitro for modulation of MHC I and II expression. these astrocytes will be tested for loss of disease. BDV antigen-specific T cell lines have been developed to serve as effector cells in these assays. Through parabiosis (surgically joined rats which share a common immune system), an in vivo model is available to determine whether the inflammatory cells from a rat with acute disease respond to the BDV infected neural cells of a rat with chronic disease or PTI by producing inflammation or disease.