Borna disease virus (BDV), a (zoonotic?) worldwide pathogen. A review of the history of the disease and the virus infection with comprehensive bibliography.

A comprehensive history of Borna disease virus (BDV) and this infection, including the complete bibliography, is presented. Over the last 200 years, descriptions of this 'head disease' of horses ('Kopfkrankheit der Pferde') have been given. Considerable losses in the horse population (< 0.8%) led to intensive clinical and (neuro-)pathological investigations of this meningitis cerebrospinalis which occurs with faint behavioural changes, occasionally followed by severe neurological symptomatology and death. The broad experimental host range reflects infections in nature which include horses, sheep, cattle, cats, dogs, rodents, ostriches, and some zoo animals. BDV infections are associated with phylogentically old brain areas, and the retina. Occasionally, expression in the autonomic nervous system occurs, besides its neurotropism BDV can spread to peripheral organs, especially to epithelial tissues and peripheral blood mononuclear cells. Infections of humans that can be monitored by antibodies, antigens or nucleic acids in blood samples are prominent features of future interest. BDV, the prototype of the family Bornaviridae is an enveloped spherical virus carrying an 8.9 kb single-stranded, non-segmented RNA with negative polarity which replicates in the nucleus. These features together with its considerable genetic stability make this non-cytopathogenic virus an evolutionary 'old pathogen' in nature.

Sequence characterization of human Borna disease virus.

Borna disease virus (BDV) causes a central nervous system disease in several vertebrate animal species, which is manifest by behavioral abnormalities. Seroepidemiologic data suggest that BDV might infect humans, possibly being associated with certain mental disorders. This is further supported by the detection of both BDV-specific antigens and RNA sequences in peripheral blood mononuclear cells (PBMCs) of psychiatric patients. For the first time the sequence characterization of human BDV is documented here. BDV was recovered by co-cultivation techniques from the PBMCs of three hospitalized psychiatric patients. BDV was unequivocally identified based on sequence identification of BDV open reading frames (ORFs) p24, p16 and p56, as well as of the predicted catalytic domain of the BDV L polymerase. Each human BDV isolate had an unique sequence, but they displayed a high degree of sequence conservation with respect of BDV isolates from naturally infected animals of different species.

First isolates of infectious human Borna disease virus from patients with mood disorders.

Borna disease virus (BDV), an unique type of non-segmented negative-stranded enveloped RNA virus, is known as an animal pathogen that causes behavioral diseases in higher vertebrates. Past studies have found antibodies to BDV as well as BDV proteins and genomic transcripts in peripheral blood mononuclear cells (PBMCs) of infected animals and human psychiatric patients. Here, we present the first isolation of infectious BDV from such patients' PBMCs. Isolation attempts were conducted with randomly collected PBMC samples from 33 psychiatric inpatients, by co-cultivation and long-term passaging with a human cell line. BDV isolates were identified by infectivity, analysis of viral antigens, sequencing of one viral gene, and successful infection of animals. Three individual isolates could be recovered. They originated from two bipolar patients with acute depression, and one patient with a chronic obsessive-compulsive disorder. Rescue of human BDV required PBMC samples with strong viral antigen expression, and at least 11 subcultures per sample. Genetic and biological properties point to a close relationship of human and animal strains, but also to the uniqueness of each human isolate. Isolation of BDV from patients with major mood disorders at a time of acute depression strengthens the possibility that BDV infection is one of the environmental factors that contributes to recurrent depressive illnesses in man. These isolates represent the first three defined strains of the infectious human BDV.

Detection of Borna disease virus RNA in naturally infected animals by a nested polymerase chain reaction.

Borna disease virus in naturally infected horses, a donkey and sheep was detected for the first time by amplification of viral RNA using PCR. In contrast to a control group of healthy horses, brain tissue was positive by this assay in all animals with neurological symptoms. The use of a second round of PCR with nested primers following Southern hybridization confirmed the specificity and increased the sensitivity of the test. Comparison with conventional methods recommends this technique for monitoring of BDV infections at a molecular level.

Biology and neurobiology of Borna disease viruses (BDV), defined by antibodies, neutralizability and their pathogenic potential.

Borna disease viruses (BDV) isolated from more than 20 naturally infected horses, 2 sheep and a possible feline isolate were included in these studies. Most of these wild-type viruses were grown in rabbit cells. Specifically rabbit-adapted viruses establish persistent infection in immortalized cell lines of various animal species. Brain-, tissue culture-, and cell-free released viruses could all be neutralized with antibodies from naturally and experimentally infected animals (horse; hamster, rat, rabbit, mouse, and chicken), with highest titres in birds. Splenectomized rabbits, which were subsequently infected with BDV, efficiently produced high titres of neutralizing antibodies. All of the neutralizing sera and cerebrospinal fluids from infected animals inhibited tissue culture spread of BDV. Experimental infection and hyperimmunization induced antibodies directed against the major components of the soluble antigen (60, 40/38, 25 and 14.5 kD proteins). Analysis of the s-antigen complex with these sera and 6 stable monoclonal antibodies revealed that it consists of 40/38 and 25 kD proteins. Although each of these antibodies detected intracellular virus-specific structures they did not recognize outer plasma membrane antigens, showed no cross-reactivity, and had no neutralizing capacity. Unifying pathogenetic concepts of this neurotropic virus and its structural elements are discussed.