Amantadine does not have antiviral activity against Borna disease virus

We have investigated the antiviral activity of amantadine (AD) against Borna disease virus (BDV) in several culture cell systems. We present evidence that AD, in the range 5 to 10 microM, does not have antiviral activity against BDV. Treatment of BDV infected cells with AD for six days caused neither a reduction in the number of infected cells, nor a decrease in steady state levels of BDV RNA or proteins. Moreover, treatment of cells with AD prior infection did not affect BDV multiplication, whereas influenza A virus yield was less than 1% with respect to that obtained in untreated control cells.     

A known virus in animals is suspected in humans. Borna disease virus has been detected in human neuropathy

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.     

Effect of interstitial cystitis on drug absorption from urinary bladder

Borna disease (BD) is a virus-induced immunopathologic disease of the central nervous system in a variety of species from birds to primates and probably in humans. Severe inflammatory reactions lead to tissue destruction and finally to cortical brain atrophy. After experimental infection of the rat, intraparenchymal CD8+ T cells, MHC class I Ags on Borna disease virus (BDV)-infected neurons, and numerous nerve cell lesions were present. Treatment of BDV-infected rats with the mAb OX-8 directed against CD8+ cells inhibited the immunopathologic reactions and reduced MHC class I Ag expression. Neuronal lesions were minimal and no loss of brain substance could be observed. Because BDV has no acute cytopathic effects, we provide evidence that the presence of CD8+ T cells within the brain parenchyma and the expression of MHC class I Ags on neurons play a major role for immunopathologic brain tissue destruction and virus-infected neurons in vivo can be destroyed by T cell-mediated cytotoxicity.     

Viral teratogenesis: brain developmental damage associated with maturation state at time of infection

The rat brain continues to mature after birth and is particularly vulnerable to developmental damage following perinatal insult. Borna disease virus (BDV) infection of postnatal day one (PND-1) rat brain causes a non-encephalitic, persistent infection associated with developmental neuroanatomical and behavioral abnormalities. To test the hypothesis that BDV infection during different brain developmental stages yields variable pathological and clinical disease sequelae, rats were examined for BDV-induced neuroanatomical and behavioral abnormalities following inoculation with BDV on PND-15, and the findings were compared to those resulting from inoculation on PND-1. Similar to rats inoculated with BDV on PND-1, PND-15 inoculated rats developed a persistent infection associated with body weight stunting, abnormal salt taste preference and hippocampal neuron degeneration. However, unlike rats infected with BDV on PND-1, PND-15 inoculated rats did not show signs of cerebellar hypoplasia or hyperactivity. Thus, the risk of BDV-induced damage to specific brain regions, and their associated behaviors, appears, in part, dependent upon the brain's developmental stage at time of BDV-infection. These studies provide evidence of the selective vulnerability of specific neuroanatomic regions and behaviors in developing nervous system to virus-induced damage.     

Evaluation of serological diagnosis of Borna disease virus infection using recombinant proteins in experimentally infected rats

We produced two recombinant Borna disease virus (BDV) proteins, p40 and p24, by using a baculovirus vector as a diagnostic antigen. Antigenicities of these recombinant proteins were evaluated by immune rabbit sera. Recombinant p40 was a more sensitive antigen than p24 for the detection of antibodies in infected rats. Rats inoculated with BDV within 24 hr after birth showed higher detection rates of viral RNA and viral proteins from the brain than rats inoculated at 4 weeks-old. Depending on the age of infection and the time postinfection, the detection of BDV RNA, protein, or anti-BDV antibody did not always correlate in individuals. We suggest both serological and molecular biological methods are needed in the diagnosis of BDV infection.     

Latero-cervical tumors: apropos of a case of paraganglioma of the vagus nerve]

Borna disease virus (BDV) is a neurotropic, as yet unclassified, non-segmented, negative-sense, single-strand RNA virus. Natural infection with this virus has been reported to occur in horses and sheep. In addition, antibodies to BDV in plasma or BDV RNA in peripheral blood mononuclear cells (PBMCs) were also found in patients with neuropsychiatric diseases. We describe here the possible link between the patients with chronic fatigue syndrome (CFS) and infection with BDV.     

Borna disease virus and the brain

Viruses with the ability to establish persistent infection in the central nervous system (CNS) can induce progressive neurologic disorders associated with diverse pathological manifestations. Clinical, epidemiological, and virological evidence supports the hypothesis that viruses contribute to human mental diseases whose etiology remains elusive. Therefore, the investigation of the mechanisms whereby viruses persist in the CNS and disturb normal brain function represents an area of research relevant to clinical and basic neurosciences. Borna disease virus (BDV) causes CNS disease in several vertebrate species characterized by behavioral abnormalities. Based on its unique features, BDV represents the prototype of a new virus family. BDV provides an important model for the investigation of the mechanisms and consequences of viral persistence in the CNS. The BDV paradigm is amenable to study virus-cell interactions in the CNS that can lead to neurodevelopmental abnormalities, immune-mediated damage, as well as alterations in cell differentiated functions that affect brain homeostasis. Moreover, seroepidemiological data and recent molecular studies indicate that BDV is associated with certain neuropsychiatric diseases. The potential role of BDV and of other yet to be uncovered BDV-related viruses in human mental health provides additional impetus for the investigation of this novel neurotropic infectious agent.     

A functional role for neutralizing antibodies in Borna disease: influence on virus tropism outside the central nervous system

Borna disease virus (BDV) is a negative-strand RNA virus that infects the central nervous systems (CNS) of warm-blooded animals and causes disturbances of movement and behavior. The basis for neurotropism remains poorly understood; however, the observation that the distribution of infectious virus in immunocompetent rats is different from that in immunoincompetent rats indicates a role for the immune system in BDV tropism: whereas in immunocompetent rats virus is restricted to the central, peripheral, and autonomic nervous systems, immunoincompetent rats also have virus in nonneural tissues. In an effort to examine the influence of the humoral immune response on BDV pathogenesis, we examined the effects of passive immunization with neutralizing antiserum in immunoincompetent rats. Serum transfer into immunoincompetent rats did not prevent persistent CNS infection but did result in restriction of virus to neural tissues. These results indicate that neutralizing antibodies may play a role in preventing generalized infection with BDV.     

Sensitivity and reproducibility of RT-PCR to detect Borna disease virus (BDV) RNA in blood: implications for BDV epidemiology

Borna disease virus (BDV) infection of domestic animals and humans appears to have a worldwide distribution. There is evidence suggesting an association of BDV with certain psychiatric disorders. However, more comprehensive epidemiological studies are required to establish rigorously a link between BDV and human mental disorders, and to evaluate the role of carrier animals as potential source of BDV for human infection. The use of RT-PCR to detect BDV RNA in peripheral blood mononuclear cells (PBMCs) of infected individuals is a powerful tool to address these questions. The comparison of discrepant results reported by different investigators using this approach is hampered by the lack of controls to assess the sensitivity and reproducibility of the assays. Procedures are now described that allow the establishment of standardized controls to evaluate the performance of the RT-PCR assays. This RT-PCR assay detected reproducibly 100 copies of BDV p40 RNA in 5 microg of RNA. The data illustrate that the number of PBMCs used for RNA preparation, rather than the amount of RNA, has a critical influence on the outcome of the RT-PCR assay. Evidence is provided that levels of BDV in blood do not necessarily reflect viral load in brain.     

The neuropathogenesis of Borna disease virus infections

The unique genetic and biological properties of this small enveloped RNA virus indicate that Borna disease virus (BDV) is an evolutionary old pathogen. It appears perfectly adapted to persist inside the limbic system, a most delicate and sensitive old area of the mammalian brain involved in the control of mood, behavior, and memory. In many infected individuals, BDV remains a commensal during their lifetime. In a minority of vulnerable subjects, BDV becomes frequently activated, leading to episodes of distinct, more or less severe disturbances of information processing, behavioral and mood alterations. BDV research in humans is anticipated to initiate new insights into the interplay of exogenous and endogenous factors governing mood disorders. In nature BDV preferentially behaves as a neurotropic virus, but may latently and/or persistently infect cells of the reticuloendothelial system. This has been shown to be of great diagnostic importance, because now BDV 'footprints' can be followed in vivo in animals and man. BDV, which has long been considered as a classical animal virus, is present in humans, and has been found to be associated with some defined psychiatric disorders in particularly vulnerable individuals. An interaction of BDV proteins with neurotransmitter activities is plausible in the light of experimental animal data. Interference with normal behavior and the influence on mood and cognitive functions as demonstrated in animals and assumed in humans require extensive future research on the molecular etiopathogenesis. Aside from these clinical aspects, BDV is an unusual agent with outstanding features, namely replication in the nucleus of its target cells by an elusive, partially unknown mechanism, showing no cytopathogenicity or disturbance of vital cell functions, but altering luxury functions, and with a lifelong persistence giving rise to periods of long latency and short activation.     

Natural Borna disease in domestic animals others than horses and sheep

In 24 cats (Uppsala, Sweden) with neurological signs of "staggering disease" and typical neuropathology, 44% had Borna disease virus (BDV)-specific antibodies. In 173 cat sera (Berlin, Germany) of animals with unknown record, 7% were BDV positive. Out of 24 cats with undefined neurological disorders, 13% were BDV positive. Similarities in staggering disease of cats and Borna disease of horses and sheep suggest related etiological agents.     

Fine structure and morphogenesis of Borna disease virus

Borna disease virus (BDV), a negative nonsegmented single-stranded RNA virus, has not been fully characterized morphologically. Here we present what is to our knowledge the first data on the fine ultrastructure and morphogenesis of BDV. The supernatant of MDCK cells persistently infected with BDV treated with n-butyrate contained many virus-like particles and more BDV-specific RNA than that of untreated samples. The particles were spherical, enveloped, and approximately 130 nm in diameter; had spikes 7 nm in length; and reacted with BDV p40 antibody. A thin nucleocapsid, 4 nm in width, was present peripherally in contrast to the thick nucleocapsid of hemagglutinating virus of Japan. The BDV particles reproduced by budding on the cell surface.     

Spontaneous Borna disease in sheep and horses: immunophenotyping of inflammatory cells and detection of MHC-I and MHC-II antigen expression in Borna encephalitis lesions

Borna disease (BD) has been recognized as a virally induced T-cell dependent immunopathological disorder of the central nervous system (CNS), as shown by experimental infection of rats with Borna disease virus (BDV). In contrast to the rat model, little is known about the pathogenesis of spontaneous BD in sheep and horses. The present study describes the brain lesions of 12 ovine and 11 equine cases of naturally occurring BD. A set of monoclonal and polyclonal antibodies was used in order to determine the cells operative in encephalitic lesions and to detect expression of MHC-I and MHC-II products in the brains of affected animals. In all cases investigated, a reaction pattern similar to that reported for the acute phase of BD in experimentally infected rats was noted. In brief, the majority of inflammatory cells in perivascular infiltrates (PVI) as well as parenchymal and meningeal infiltrates were CD3 +. CD4 + cells outnumbered CD8 + cells in PVI as well as in the parenchyma. Macrophages (defined by lysozyme immunoreactivity) were seen less often and B-cells or plasma cells (cells positive for lambda or kappa light chains) were demonstrated at lower numbers. TCR-1 + cells were found on very rare occasions in PVI of some sheep. MHC-I and MHC-II products were constantly expressed on inflammatory cells but inconsistently on astrocytes and neurons. Neuronal degeneration was not a major feature.