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Borna disease virus is the prototype of a new family, Bornaviridae, within the order Mononegavirales, that is characterized by nuclear transcription, splicing, low level replication, and neurotropism. The products of five open reading frames predicted from the genomic sequence have been confirmed; however, expression of the sixth, corresponding to the putative viral polymerase (L), has not been demonstrated. Here, we describe expression and characterization of a 190-kDa protein proposed to represent L. Expression of this protein from the third transcription unit of the viral genome is dependent on a splicing event that fuses a small upstream open reading frame in frame with the larger downstream continuous open reading frame. The protein is detected by serum antibodies from infected rats and is present in the nucleus, where it colocalizes with the phosphoprotein. L is also shown to be phosphorylated by cellular kinases and to interact with the viral phosphoprotein in coimmunoprecipitation studies. These findings are consistent with the identity of the 190-kDa protein as the viral polymerase and provide insights and describe reagents that will be useful for Bornavirus molecular biology and pathobiology.

Lewis rats neonatally infected with Borna disease virus have a behavioral syndrome characterized by hyperactivity, movement disorders, and abnormal social interactions. Virus is widely distributed in brain; however, neuropathology is focused in dentate gyrus, cerebellum, and neocortex where granule cells, Purkinje cells and pyramidal cells are lost through apoptosis. Although a transient immune response is present, its distribution does not correlate with sites of damage. Neuropathology is instead colocalized with microglial proliferation and expression of MHC class I and class II, ICAM, CD4 and CD8 molecules. Targeted pathogenesis in this system appears to be linked to microglial activation and susceptibility of specific neuronal populations to apoptosis rather than viral tropism or virus-specific immune responses.

Although the question of human BDV infection remains to be resolved, burgeoning interest in this unique pathogen has provided tools for exploring the pharmacology and neurochemistry of neuropsychiatric disorders potentially linked to BDV infection. Two animal models have been established based on BDV infection of adult or neonatal Lewis rats. Analysis of these models is already yielding insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior.

Perinatal exposure to infectious agents and toxins is linked to the pathogenesis of neuropsychiatric disorders, but the mechanisms by which environmental triggers interact with developing immune and neural elements to create neurodevelopmental disturbances are poorly understood. We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. Infection results in abnormal righting reflexes, hyperactivity, inhibition of open-field exploration, and stereotypic behaviors. Architecture is markedly disrupted in hippocampus and cerebellum, with reduction in granule and Purkinje cell numbers. Neurons are lost predominantly by apoptosis, as supported by increased mRNA levels for pro-apoptotic products (Fas, caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in situ labeling of fragmented DNA. Although inflammatory infiltrates are observed transiently in frontal cortex, glial activation (microgliosis > astrocytosis) is prominent throughout the brain and persists for several weeks in concert with increased levels of proinflammatory cytokine mRNAs (interleukins 1alpha, 1beta, and 6 and tumor necrosis factor alpha) and progressive hippocampal and cerebellar damage. The resemblance of these functional and neuropathologic abnormalities to human neurodevelopmental disorders suggests the utility of this model for defining cellular, biochemical, histologic, and functional outcomes of interactions of environmental influences with the developing central nervous system.

Chronic Fatigue Syndrome (CFS) is characterized by debilitating fatigue, somatic symptoms and cognitive impairment. An infectious basis has been proposed; candidate agents include enteroviruses, herpesviruses, retroviruses and Borna disease virus (BDV), a novel neurotropic virus associated with neuropsychiatric disorders. Sera and peripheral blood mononuclear cells (PBMC) from Swedish CFS patients were assayed for evidence of infection using ELISA and Western immunoblot for detection of antibodies to BDV proteins N, P and gp18; and using nested reverse transcriptase polymerase chain reaction (RT-PCR) for detection of BDV N- and P-gene transcripts. No specific immunoreactivity to BDV proteins was found in sera from 169 patients or 62 controls. No BDV N- or P-gene transcripts were found through RT-PCR analysis of PBMC from 18 patients with severe CFS. These results do not support a role for BDV in pathogenesis of CFS.

The guanosine analogue ribavirin was tested for antiviral activity in two neural cell lines, human oligodendrocytes and rat glia, against Borna disease virus (BDV) strains V and He/80. Ribavirin treatment resulted in lower levels of virus and viral transcripts within 12 h. Addition of guanosine but not adenosine resulted in a profound reduction of the ribavirin effect. Ribavirin appears to be an effective antiviral agent for treatment of BDV infection in vitro. A likely mechanism for its activity is reduction of the intracellular GTP pool, resulting in inhibition of transcription and capping of BDV mRNAs.

Borna disease virus (BDV) is a neurotropic virus with a broad host and geographic range. Lewis rats were immunized against BDV with a recombinant vaccinia virus expressing the BDV nucleoprotein and were later infected with BDV to evaluate protection against Borna disease (BD). Relative to animals that were not immunized, immunized animals had a decreased viral burden after challenge with infectious virus, more marked inflammation, and aggravated clinical disease. These data suggest that a more robust immune response in Borna disease can reduce viral load at the expense of increased morbidity.

Borna disease virus (BDV) is a newly classified non-segmented neurotrophic negative-strand RNA virus with a worldwide distribution and affecting warm-blooded animals ranging from birds to primates. Infection may be asymptomatic or results in manifest disturbances of movement behaviour. Although BDV has not been unequivocally implicated in any human disease, several reports have suggested relationship to exist between BDV infection and certain neuropsychiatric syndromes including affective disorders, chronic fatigue syndrome, and schizophrenia. Moreover, at least one centre has initiated a trial of antiviral therapy in patients with affective disorders attributable to BDV. The article consists in a review of recent advances in the molecular biology, pathogenesis and epidemiology of BDV, and an outline of anticipated directions for future research.

Borna disease virus, a newly classified nonsegmented negative-strand RNA virus with international distribution, infects a broad range of warm-blooded animals from birds to primates. Infection causes movement and behavioral disturbances reminiscent of some neuropsychiatric syndromes. The virus has not been clearly linked to any human disease; however, an association between infection with the virus and selected neuropsychiatric disorders has been suggested. We reviewed recent advances in Borna disease virus research, focusing on evidence of infection in humans.

Viruses have been proposed to play a role in the pathogenesis of schizophrenia; however, the mechanisms by which infection could cause the affective, cognitive, and movement disorders of schizophrenia are not understood. The neurotropic RNA virus, Borna disease (BD) virus, linked to schizophrenia by serologic studies, causes movement and behavior disorders in a wide variety of mammalian and bird hosts. BD rats have hyperactivity and stereotyped behaviors similar to those that follow neurotoxic or electrolytic lesions in frontal cortex or its catecholamine afferents in rats. BD rats have high levels of viral nucleic acid in the prefrontal cortex (PFC), abnormal mesocortical dopamine activity (elevated levels of DOPAC in PFC), yet no alteration in specific binding of D1 or D2 receptor radioligands in PFC. Since frontal lobe dysfunction is frequently reported in schizophrenia, the BD rat model may provide insights into pathogenesis and management of this debilitating psychiatric disease.

Rats experimentally infected with the neurotropic RNA virus, Borna disease virus, have a hyperactive movement disorder. Because locomotor activity is modulated by the nucleus accumbens (N. Acc.) dopamine (DA) system, high-affinity DA uptake, DA D1, D2, and D3 receptor binding sites were examined in N. Acc. subregions of normal and infected rats by quantitative receptor autoradiography. The N. Acc. of infected rats had decreased mazindol and D2 and D3 radioligand binding in the core and decreased D3 radioligand binding in rostral subregions. The abnormalities observed in the N. Acc. DA system of infected rats may offer insights into the potential viral pathogenesis of psychiatric conditions with a dopaminergic substrate such as schizophrenia and affective disorders.

Borna disease virus (BDV) is a neurotropic agent that causes disturbances in movement and behavior in vertebrate host species ranging from birds to primates. Although the virus has not been isolated from human subjects, there is indirect evidence to suggest that humans with neuropsychiatric disorders may be infected with BDV. Recently, virus particles have been isolated and the viral genomic RNA has been cloned. This analysis revealed that BDV is a nonsegmented, negative-strand RNA virus. Unusual features such as RNA splicing, overlap of transcription units and transcription signals, as well as sequence dissimilarity for four of five major open reading frames to genes of other nonsegmented, negative-strand RNA viruses suggest that BDV is likely to represent a new taxon within the order Mononegavirales.

Tissues from 9 horses and 1 donkey suffering from natural Borna disease were investigated immunomorphologically. Lymphocytic inflammatory reactions and increased expressions of MHC class I and class II antigen were found in the brain as well as in the trigeminal and olfactory system. Perivascular inflammatory infiltrates were dominated by CD4+ T cells, whereas the majority of CD8+ T cells were disseminated intraparenchymally. No evidence of inflammation was found in the retina. Borna disease virus proteins and nucleic acids were present in the hippocampus, thalamus and medulla oblongata in all 10 animals, in the cerebral cortex, retina, trigeminal ganglion and nerve in 9, in the olfactory epithelium in 6 and in roots and proximal parts of large peripheral nerves in 3. No evidence of infection was found in the autonomic nervous system, lung, heart, liver, kidney or gut. BDV- proteins and nucleic acids were even more abundant in the trigeminal system than in the olfactory system, suggesting that infection may have occurred via the trigeminal nerve.

BDV uses a remarkably broad range of mechanisms to direct expression of its 8.9-kb genome. Although much remains to be elucidated, it is clear that BDV genome expression is modulated by the use of multiple strategies, including differential gene transcription, post-transcriptional modification, and translational efficiency. Further insights into the details of this multilevel system will be essential to understanding BDV biology, pathogenesis, and neurotropism.

The cause of Borna disease, a neurological syndrome affecting mammals and birds, has recently been shown to be infection with an RNA virus. Molecular genetic analysis suggests that Borna disease virus represents a new viral taxon. It has a wide host range and is tropic for specific circuits in the central nervous system. There is indirect evidence that links it to diseases of the human central nervous system.

Tardive Dyskinesia (TD) is a hyperkinetic movement disorder caused by chronic treatment of psychiatric patients with dopamine (DA) receptor blocking drugs (Stacy & Jankovic 1991). Although TD is one of the most important and frequently encountered iatrogenic disorders in clinical medicine, its pathophysiology is poorly understood. We have observed a hyperkinetic movement disorder in rats experimentally infected with a neurotropic RNA virus, Borna disease virus, that may provide important insights into the pathophysiology of TD. Like TD patients, infected rats show prominent orofacial dyskinesias. In keeping with the dopamine (Goetz & Klawans 1982) and anatomic (Fibiger & Lloyd 1984) hypotheses of TD, the Borna disease rat model shows enhanced behavioural sensitivity to DA agonists and selective striatal cell damage. There is also evidence of DA deafferentation and heterogeneous reduction of D2 binding in the caudate-putamen, particularly from sites implicated in oral behaviour. These observations on a virus-induced movement disorder offer novel approaches to TD pathogenesis.

Borna disease (BD) is an immune-mediated neurological disease caused by infection of the nervous system with a negative strand RNA virus, Borna disease virus (BDV). The host range for BDV is broad and extends from birds to primates. A BDV-like agent may cause disease in humans. Until recently, BDV-infected neural cells could only be identified immunocytochemically using serum from BDV-infected animals. The advent of BDV cDNA clones allowed definition of the relationship between viral nucleic acids and viral proteins in vivo. In situ hybridization with strand-specific RNA probes from a BDV cDNA clone, pAF4, identified BDV genomic RNA and BDV mRNAs in neurons, astrocytes, Schwann cells and ependymal cells in an anatomic distribution consistent with that of BDV proteins. Genomic RNA was contained primarily within the nucleus, whereas mRNAs were found in both the nuclear and cytoplasmic compartments. Viral RNAs were demonstrated in neurons expressing BDV proteins and in glial cells by combined techniques of immunocytochemistry and in situ hybridization.

Borna disease (BD) is a neurologic syndrome characterized by profound disturbances in behavior and the accumulation of specific antigens in limbic system neurons. The potency of brain homogenates from animals with BD to cause disease in normal animals is reduced by exposure to detergents. We have recently described isolation and characterization of clones derived from the BD agent. Here we present evidence that suggests that the BD agent is a negative-sense, single-strand RNA virus. The 8.5-kb genome of this virus appears to be associated with nuclei and encodes two major RNA transcripts of 2.1 and 0.8 kb.

We describe a method which uses protein blots of whole animal sections to map the distribution of exogenous and endogenous antigens to specific nuclei and tracts within the nervous system (NS). We propose this method as a new approach to analysis of the expression of NS gene products during development and to charting the course and molecular pathogenesis of infectious and immune disorders of the NS.

Neonatal mice inoculated with lymphocytic choriomeningitis virus (LCMV) have non-lytic persistent neuronal infection and disturbed behavior. We now show that LCMV replicates in neurons containing the neurotransmitter somatostatin without morphologic evidence of injury and that persistent neuronal LCMV infection in mice is attended by a decrease in brain levels of somatostatin mRNA. Brain levels of mRNA for another neurotransmitter peptide, cholecystokinin, are not decreased. These data are the first to localize a virus to a specific neurotransmitter-containing cell during in vivo infection and suggest that persistent viral infections could cause neurologic or psychiatric diseases through selective effects on brain levels of neurotransmitter mRNAs.

Borna disease (BD) agent is an infectious pathogen that causes progressive central nervous system (CNS) dysfunction in a wide range of vertebrate hosts. The course of BD in adult rats is biphasic. The acute phase is characterized by aggressive behavior and inflammatory cell infiltrates in brain. With chronic infection animals become listless and inflammation resolves. BD antigens are similarly distributed in neurons in hippocampus, neocortex, cerebellum and brainstem in acutely and chronically infected animals. We have recently examined brain levels of neuronal transcripts in rats with acute and chronic BD. Levels for 3 of these mRNAs, cholecystokinin, glutamic acid decarboxylase and somatostatin, were decreased in acutely infected rats and increased toward control values in chronically infected rats. A fourth transcript, MuBr8, correlated in distribution with BD antigen, was persistently decreased throughout the course of infection. These data may have implications for understanding the pathogenesis of neurologic disturbances in BD and other inflammatory CNS diseases.

Nucleic acid hybridization and protein blotting procedures have allowed the specific detection of both RNA and protein gene products in whole body sections of a selected host. These procedures permit efficient and reproducible screening of both endogenous and exogenous (viral) gene products, thus facilitating the study of normal differentiation, the localization of virus and the monitoring of viral diseases. Although success with RNA hybridization has thus far been limited to exogenous viral gene expression, the protein immunoblotting procedures have the sensitivity to detect endogenous protein products with high resolution. These combined procedures should prove useful for the study of protein expression in numerous developmental systems.