borna virus in psychiatric patients


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(Updated 1/13/04)

Ludwig H, Bode L.
Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology.
Rev Sci Tech. 2000 Apr;19(1):259-88.
"A 'disease of the head' affecting horses, as described in the 17th Century is now known as Borna disease. Research over the past 100 years has established that the aetiological agent, Borna disease virus (BDV), is an unsegmented, single- and negative-stranded, enveloped ribonucleic acid (RNA) virus which represents the family Bornaviridae in the order Mononegavirales. The virus exists world-wide in horses, sheep, cattle, cats, dogs and ostriches. The infection can be fatal, but the majority of carriers are persistently infected without showing symptoms. The association with psychiatric diseases in humans led to an international explosion of research on BDV, with centres established in Germany, the United States of America and Japan. Experimental infections of tree shrews and rats served to examine the effects of persistent and overt disease, most excitingly, virus-induced behavioural changes, and emotional and learning deficits. This 'emerging' virus infection shows complex pathogenetic mechanisms in the nervous system, but also spreads through myelo-monocytic cells. Diagnosis can be made serologically, but detection of antigen markers in peripheral white blood cells, combined with nucleic acid amplification is more profitable. Comparative RNA studies reveal an unusually high genetic homology of viruses. Isolates recovered from humans and equines suggest species-specificity. Vaccination is not an advisable strategy, but antiviral therapy, especially with amantadine sulphate, promises efficacy in human mood disorders, and is effective in vitro. Infections with BDV follow a vulnerability principle to cause disease. Although cross-species transmission of this commensal virus has not been proven, zoonotic aspects of BDV should be carefully considered." [Abstract]

Bode L, Ludwig H.
Borna disease virus infection, a human mental-health risk.
Clin Microbiol Rev. 2003 Jul;16(3):534-45.
"This article focuses on human Borna disease virus (BDV) infections, most notably on the development of valid diagnostic systems, which have arisen as a major research issue in the past decade. The significance of a novel modular triple enzyme-linked immunosorbent assay that is capable of specifically measuring anti-BDV antibodies as well as major structural proteins N (p40) and P (p24) in the blood, either as free antigens in the plasma or as antibody-bound circulating immune complexes (CICs), is explained. The impact of CICs and plasma antigen, which indicate periods of antigenemia in the course of BDV infection, along with other infection markers that are still in use is discussed. The review further provides new insight into possible links of BDV to human diseases, summarizing cross-sectional and longitudinal data which correlate acute depression with the presence and amount of antigen and CICs. Moreover, BDV prevalence in healthy people is reevaluated, suggesting that this was previously underestimated. Antiviral efficacy of amantadine, in vivo and in vitro, is outlined as well, with emphasis on wild-type (human and equine) versus laboratory strains. Finally, the pros and cons of the association of BDV with human disease, as detailed in the literature, are critically discussed and related to our data and concepts. This article supports existing correlative evidence for a pathogenic role of BDV infection in particular human mental disorders, in analogy to what has been proven for a variety of animal species." [Abstract]

Dietrich DE, Schedlowski M, Bode L, Ludwig H, Emrich HM.
A viro-psycho-immunological disease-model of a subtype affective disorder.
Pharmacopsychiatry. 1998 May;31(3):77-82.
"Borna Disease Virus (BDV) infections are widespread in animal species. This neurotropic, negative and single-stranded enveloped RNA virus spreads via axonal and transsynaptic pathways quite specifically into olfactoric and limbic structures. The symptoms in BDV-infected animals range from unapparent or subtle clinical manifestations to fatal neurological disorders. The severe and fulminant course of the infection, which is often accompanied by neurobehavioral and "emotional" disturbances, occurs sporadically and, at least in experimentally infected animals (rats), is thought to be mediated by immunopathology. Increases in serum-BDV antibodies have also been detected in neuropsychiatric patients. In addition, viral antigen and viral RNA have been observed in acutely ill major depressive patients, leading to the conclusion that BDV was causally related to psychiatric disorders, in particular to affective disorders. A number of studies have meanwhile furnished evidence of abnormal immune functions in mentally ill patients. In addition, stress has been shown to decrease immune responses to viral infections. On the basis of these findings it is hypothesized that human BDV infection represents a co-factor in the development or course of psychiatric diseases. Stress may cause immunosuppression and thus induce activation of persisting BDV in the limbic system, resulting in an inflammatory reaction of these structures. These neuropathological changes might influence the serotonergic or dopaminergic neurotransmitter systems. In addition, a specific affinity of BDV structural elements for aspartate and glutamate receptors in the hippocampal formation might directly induce an imbalance of these transmitter system interactions, causing affective and behavioral disturbances. The possible interactions between stress-induced immunosuppression, BDV infection and affective disorders in humans, and the theoretical and clinical aspects of this concept are discussed." [Abstract]

Billich C, Sauder C, Frank R, Herzog S, Bechter K, Takahashi K, Peters H, Staeheli P, Schwemmle M.
High-avidity human serum antibodies recognizing linear epitopes of Borna disease virus proteins.
Biol Psychiatry. 2002 Jun 15;51(12):979-87.
"BACKGROUND: The recent observation that Borna disease virus (BDV)-reactive antibodies from psychiatric patients exhibit only low avidity for BDV antigen called into question their diagnostic value and raised the possibility that antigenically related microorganisms or self antigens caused the production of these antibodies. We further characterized the specificity of these antibodies.METHODS: We established a peptide array-based screening test that allows the identification of antibodies directed against linear epitopes of the two major BDV proteins, the nucleoprotein (N) and the phosphoprotein (P).RESULTS: Initial tests employing sera of BDV-infected mice and rats or horses with Borna disease revealed a high specificity and sensitivity of this test. All sera recognized epitopes of N, P, or both. Sera of noninfected rats, mice, and horses showed no signals on either peptide array. Several human sera that recognized BDV antigen by indirect immunofluorescence contained antibodies that recognized various linear epitopes of one or even both BDV proteins. Remarkably, antibodies purified from such human serum by matrix-immobilized peptides showed high-avidity binding to BDV antigens when assayed by IFA or Western blotting.CONCLUSIONS: These data suggest that reactive antibodies found in psychiatric patients indeed indicate infection with BDV or a BDV-like agent. However, the poor affinity maturation of BDV-specific human antibodies remains unexplained." [Abstract]

Allmang U, Hofer M, Herzog S, Bechter K, Staeheli P.
Low avidity of human serum antibodies for Borna disease virus antigens questions their diagnostic value
Mol Psychiatry. 2001 May;6(3):329-33.
"Borna disease virus (BDV) can induce neurological disease in animals. Since viral nucleic acid, infectious particles and antibodies recognizing BDV antigens were found at higher frequencies in psychiatric patients than in healthy controls, BDV is suspected to cause psychiatric disorders in humans. However, the human origin of these viruses has recently been questioned. To diagnose BDV infections, sera are usually analyzed for antiviral antibodies by indirect immunofluorescence (IFA) on virus-infected cells. This study reveals that the reactive antibodies in human sera mainly recognized the BDV phosphoprotein, whereas animal sera preferentially detected the viral nucleoprotein. Immunoglobulin (Ig) G in sera of experimentally or naturally infected animals bound to the viral antigen with high avidity, ie resisting 3 M urea, whereas reactive IgG in human sera did not. Longitudinal studies showed that reactive human antibodies persisted for many years without gaining high avidity for BDV antigens, indicating that they were probably not induced by BDV but rather by infection with an antigenically related microorganism of unknown identity or by exposure to other related immunogens." [Abstract]

Carbone KM.
Borna disease virus and human disease.
Clin Microbiol Rev. 2001 Jul;14(3):513-27.
"The biology of Borna disease virus (BDV) strongly supports the likelihood of human infection with BDV or a variant of BDV. Thus far, the evidence supporting BDV infection in humans has initiated much controversy among basic and clinical scientists; only time and additional research will support or refute the hypothesis of human BDV infection. Until an assay of acceptable specificity and sensitivity has been developed, validated, and used to document human BDV infection, scientists cannot reasonably begin to associate BDV infection with specific disease syndromes. Clinical studies seeking causal associations between BDV infection and specific diseases must ensure the proper identification of the BDV infection status of patients and control subjects by using a validated, highly sensitive, and highly specific assay (or series of assays). For clinical studies, a highly sensitive "screening" test followed by a highly specific confirmatory test will be of significant benefit. Although it is possible to formulate hypotheses about the clinical outcomes of human BDV infection based on animal model work, to date no human disease has been causally linked to human BDV infection. Scientists all over the world are actively pursuing these issues, and with continuing advances in clinical and basic BDV research, the answers cannot be far away." [Abstract]

Taieb O, Baleyte JM, Mazet P, Fillet AM.
Borna disease virus and psychiatry.
Eur Psychiatry. 2001 Feb;16(1):3-10.
"Borna disease virus (BDV), a noncytolytic neurotropic nonsegmented negative-stranded RNA virus with a wide geographic distribution, infects several vertebrate animal species and causes an immune-mediated central nervous system (CNS) disease with various manifestations, depending on both host and viral factors. In animal infections, BDV can persist in the CNS and induce alterations in brain cell functions, neurodevelopmental abnormalities and behavioral disturbances. An association between BDV and psychiatric disorders (essentially schizophrenia and affective disorders) has been suggested by some serologic and molecular studies but further investigations are required to substantiate the possible contribution of this virus to the pathogenesis of these disorders." [Abstract]

Ikuta K, Ibrahim MS, Kobayashi T, Tomonaga K.
Borna disease virus and infection in humans.
Front Biosci. 2002 Feb 1;7:d470-95.
"Borna disease virus (BDV) is a nonsegmented, negative-, single-stranded, highly neurotropic RNA virus with noncytolytic replication in the central nervous system. This virus causes neurological and behavioral disturbances primarily in horses and sheep, in addition to a variety of other vertebrate animal species and in laboratory animal models. BDV is now gaining much of the research attention, because the disturbances seen in animals resemble those of neuropsychiatric disorders in humans. These observations raise the possibility that BDV infection may be associated with certain human disorders. Serological and molecular studies on many samples from human patients with a variety of psychiatric disorders have been performed. Some reported the presence and elevated levels of serum antibodies to BDV. Others reported the presence of BDV-RNAs or BDV-antigens in the peripheral blood samples as well as in autopsied brains. Taken together these data support the possibility of human infection with BDV. On the contrary, others reported the complete absence of such BDV-markers from their samples, supporting the absence of a link between BDV infection and psychiatric disorders as well as excluding it as a human pathogen. Thus, BDV infection in humans is highly controversial. Further investigations are required to answer the question whether BDV is a human pathogen and moreover, to elucidate the possible role, if any, of BDV in the pathogeneses of these disorders." [Abstract]

Sauder C, de la Torre JC.
Sensitivity and reproducibility of RT-PCR to detect Borna disease virus (BDV) RNA in blood: implications for BDV epidemiology.
J Virol Methods. 1998 Apr;71(2):229-45.
"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." [Abstract]

Bode L, Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE, Ludwig H.
Borna disease virus-specific circulating immune complexes, antigenemia, and free antibodies--the key marker triplet determining infection and prevailing in severe mood disorders.
Mol Psychiatry. 2001 Jul;6(4):481-91.
"Borna disease virus (BDV), a unique genetically highly conserved RNA virus (Bornaviridae; Mononegavirales), preferentially targets neurons of limbic structures causing behavioral abnormalities in animals. Markers and virus in patients with affective disorders and schizophrenia have raised worldwide interest. A persistent infection was suggestive from follow-up studies, but inconstant detectability weakened a possible linkage.This study for the first time discloses that detection gaps are caused by BDV-specific circulating immune complexes (CIC), and their interplay with free antibodies and plasma antigens (p40/p24). Screening 3000 sera each from human and equine patients over the past 4 years by new enzyme immunoassays (EIAs) revealed that BDV-CICs indicate 10 times higher infection rates (up to 30% in controls, up to 100% in patients) than did previous serology. Persistence of high amounts of CICs and plasma antigens correlates with severity of depression. Even BDV RNA could be detected in plasma samples with strong antigenemia. Our discovery not only explains the course of persistent infection, but offers novel easy-to-use diagnostic tools by which new insights into BDV-related etiopathogenesis of disease and epidemiology are possible." [Abstract]

Planz, Oliver, Rentzsch, Christine, Batra, Anil, Batra, Arvind, Winkler, Tanja, Buttner, Mathias, Rziha, Hanns-Joachim, Stitz, Lothar
Pathogenesis of Borna Disease Virus: Granulocyte Fractions of Psychiatric Patients Harbor Infectious Virus in the Absence of Antiviral Antibodies
J. Virol. 1999 73: 6251-6256
"Borna disease virus (BDV) causes acute and persistent infections in various vertebrates. During recent years, BDV-specific serum antibodies, BDV antigen, and BDV-specific nucleic acid were found in humans suffering from psychiatric disorders. Furthermore, viral antigen was detected in human autopsy brain tissue by immunohistochemical staining. Whether BDV infection can be associated with psychiatric disorders is still a matter of debate; no direct evidence has ever been presented. In the present study we report on (i) the detection of BDV-specific nucleic acid in human granulocyte cell fraction from three different psychiatric patients and (ii) the isolation of infectious BDV from these cells obtained from a patient with multiple psychiatric disorders. In leukocyte preparations other than granulocytes, either no BDV RNA was detected or positive PCR results were obtained only if there was at least 20% contamination with granulocytes. Parts of the antigenome of the isolated virus were sequenced, demonstrating the close relationship to the prototype BDV strains (He/80 and strain V) as well as to other human virus sequences. Our data provide strong evidence that cells in the granulocyte fraction represent the major if not the sole cell type harboring BDV-specific nucleic acid in human blood and contain infectious virus. In contrast to most other reports of putative human isolates, where sequences are virtually identical to those of the established laboratory strains, this isolate shows divergence in the region previously defined as variable in BDV from naturally infected animals." [Full Text]

Rott R, Herzog S, Richt J, Stitz L.
Immune-mediated pathogenesis of Borna disease.
Zentralbl Bakteriol Mikrobiol Hyg [A]. 1988 Nov;270(1-2):295-301.
"Borna disease is an endemic progressive encephalomyelitis of horses and sheep prevalent in central Europe. A wide variety of animal species, ranging from chickens to primates can be infected experimentally with the causative virus, which is only poorly characterized. Furthermore, BD virus-specific antibodies have been detected in sera and cerebrospinal fluids of psychiatric patients. Our studies on the pathogenesis of BD have shown that-at least in rats-the disease is not caused by the infecting virus itself, but by a virus-induced immunopathological reaction. Thus, after intracerebral infection immunoincompetent rats do not get the disease despite persistent virus replication in cells of the central nervous system. However, after adoptive transfer of immune cells from diseased rats, immunoincompetent rats exhibit full-blown BD. Recently, we have been successful in establishing a virus-specific T cell line of the helper/inducer phenotype (CD4+). This T cell was shown to play an important role in the pathogenesis of BD, suggesting that the disease is caused by a delayed type hypersensitivity reaction." [Abstract]

de la Torre JC.
Bornavirus and the brain.
J Infect Dis. 2002 Dec 1;186 Suppl 2:S241-7. [Abstract]

Haga S, Yoshimura M, Motoi Y, Arima K, Aizawa T, Ikuta K, Tashiro M, Ikeda K.
Detection of Borna disease virus genome in normal human brain tissue.
Brain Res. 1997 Oct 3;770(1-2):307-9.
"Borna disease virus (BDV), a neurotropic virus naturally infecting horses and sheep, has been suggested to be associated with human psychiatric disorders. Thus far no extensive studies have been done, providing the evidence of BDV genome in normal human brain tissue. We therefore examined four brain regions of 30 normal autopsy brains for BDV p24 genome. By highly sensitive nested reverse transcriptase (RT)-mediated PCR analysis, we found positive PCR products in two brains: one in frontal and temporal cortices and hippocampus and another in frontal cortex and olfactory bulb. Our results suggest that BDV can infect human brain tissue latently, without causing an apparent neuropsychiatric disorder." [Abstract]

De La Torre JC, Gonzalez-Dunia D, Cubitt B, Mallory M, Mueller-Lantzsch N, Grasser FA, Hansen LA, Masliah E.
Detection of borna disease virus antigen and RNA in human autopsy brain samples from neuropsychiatric patients.
Virology. 1996 Sep 15;223(2):272-82.
"Borna disease virus (BDV) causes a central nervous system disease in several vertebrate species which is characterized by behavioral disturbances. Seroepidemiological data indicate an association of BDV infection with certain human mental disorders. Sclerosis of the hippocampus and astrocytosis constitute histopathological hallmarks of BDV infection in animals. Therefore, we searched for human brain autopsy cases with such histopathological features. Five of 600 cases examined were identified as having hippocampus sclerosis and astrocytosis. Using immunocytochemistry, RT-PCR, and in situ hybridization, we detected both BDV antigen and RNA in autopsy brain samples from 4 of these 5 patients, who presented with a clinical history of mental disorders involving memory loss and depression. This is the first demonstration that BDV can infect human brain tissue, possibly contributing to the pathophysiology of specific human neuropsychiatric disorders." [Abstract]

Nakamura, Yurie, Takahashi, Hirokazu, Shoya, Yuko, Nakaya, Takaaki, Watanabe, Makiko, Tomonaga, Keizo, Iwahashi, Kazuhiko, Ameno, Kiyoshi, Momiyama, Noriko, Taniyama, Hiroyuka, Sata, Tetsutaro, Kurata, Takeshi, de la Torre, Juan Carlos, Ikuta, Kazuyoshi
Isolation of Borna Disease Virus from Human Brain Tissue
J. Virol. 2000 74: 4601-4611
"Serological and molecular epidemiological studies indicate that Borna disease virus (BDV) can infect humans and is possibly associated with certain neuropsychiatric disorders. We examined brain tissue collected at autopsy from four schizophrenic patients and two healthy controls for the presence of BDV markers in 12 different brain regions. BDV RNA and antigen was detected in four brain regions of a BDV-seropositive schizophrenic patient (P2) with a very recent (2 years) onset of disease. BDV markers exhibited a regionally localized distribution. BDV RNA was found in newborn Mongolian gerbils intracranially inoculated with homogenates from BDV-positive brain regions of P2. Human oligodendroglia (OL) cells inoculated with brain homogenates from BDV-positive gerbils allowed propagation and isolation of BDVHuP2br, a human brain-derived BDV. Virus isolation was also possible by transfection of Vero cells with ribonucleoprotein complexes prepared from BDV-positive human and gerbil brain tissues. BDVHuP2br was genetically closely related to but distinct from previously reported human- and animal-derived BDV sequences." [Full Text]

Nakamura Y.
[Isolation of Borna disease virus from the autopsy brain of a schizophrenia patient]
Hokkaido Igaku Zasshi. 1998 May;73(3):287-97.
"Borna disease virus (BDV) causes a central nervous system disease in several vertebrate species which is characterized by behavioral disturbances. Seroepidemiological data suggested an association of BDV infection with certain human mental disorders, especially schizophrenia and depression. Here, BDV infection was examined in autopsy brain samples from 4 schizophrenia patients. Nested reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization revealed BDV-RNA only in restricted regions (hippocampus, cerebellum, pons) of the autopsy brain samples from one but not other three patients. Histopathologically mild perivascular cuffing was observed in hippocampus, in which BDV-RNA was detected. Next, BDV isolation from the BDV-positive patient's brain region was carried out by intracranial inoculation of BDV-sensitive Mongolian gerbils with the patient's cerebellum and hippocampus homogenate. BDV-RNA signals were detected in the brain from inoculated gerbils at 20 days post-inoculation by nested RT-PCR. Further, the BDV-RNA positive brain from an inoculated gerbil was used for BDV isolation in cell culture. Serial passages with human oligodendroglioma (OL) cells allowed to establish persistent infection of BDV in the cells." [Abstract]

Kamitani W, Ono E, Yoshino S, Kobayashi T, Taharaguchi S, Lee BJ, Yamashita M, Kobayashi T, Okamoto M, Taniyama H, Tomonaga K, Ikuta K.
Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice.
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8969-74. Epub 2003 Jul 11.
"One hypothesis for the etiology of behavioral disorders is that infection by a virus induces neuronal cell dysfunctions resulting in a wide range of behavioral abnormalities. However, a direct linkage between viral infections and neurobehavioral disturbances associated with human psychiatric disorders has not been identified. Here, we show that transgenic mice expressing the phosphoprotein (P) of Borna disease virus (BDV) in glial cells develop behavioral abnormalities, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit. We demonstrate that the transgenic brains exhibit a significant reduction in brain-derived neurotrophic factor and serotonin receptor expression, as well as a marked decrease in synaptic density. These results demonstrate that glial expression of BDV P leads to behavioral and neurobiological disturbances resembling those in BDV-infected animals. Furthermore, the lack of reactive astrocytosis and neuronal degeneration in the brains indicates that P can directly induce glial cell dysfunction and also suggests that the transgenic mice may exhibit neuropathological and neurophysiological abnormalities resembling those of psychiatric patients. Our results provide a new insight to explore the relationship between viral infections and neurobehavioral disorders." [Abstract]

Hornig M, Solbrig M, Horscroft N, Weissenbock H, Lipkin WI.
Borna disease virus infection of adult and neonatal rats: models for neuropsychiatric disease.
Curr Top Microbiol Immunol. 2001;253:157-77.
"Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Borna disease virus infection that provide new 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. Note in press: Since this chapter was submitted, several manuscripts have been published that extend findings reported here and support the relevance of BDV infections of neonatal Lewis rats as models for investigating mechanisms of neurodevelopmental damage in autism. Behavioral abnormalities, including disturbed play behavior and chronic emotional overactivity, have been described by Pletnikov et al. (1999); inhibition of responses to novel stimuli were described by Hornig et al. (1999); loss of Purkinje cells following neonatal BDV infection has been demonstrated by Eisenman et al. (1999), Hornig et al. (1999), and Weissenbock et al. (2000); and alterations in cytokine gene expression have been reported by Hornig et al. (1999), Plata-Salaman et al. (1999) and Sauder et al. (1999)." [Abstract]

Vahlenkamp TW, Enbergs HK, Muller H.
Experimental and natural borna disease virus infections: presence of viral RNA in cells of the peripheral blood.
Vet Microbiol. 2000 Oct 1;76(3):229-44.
"Cells of the peripheral blood of experimentally and naturally borna disease virus (BDV)-infected animals and of human psychiatric patients and healthy individuals were analyzed for the presence of viral RNA using a BDV-p40-specific nested reverse transcription-polymerase chain reaction (RT-PCR). The assay proved to be highly sensitive as 10 RNA molecules were reproducibly amplified. BDV RNA was detected in blood cells of experimentally infected immunocompetent mice and rats. Mice were persistently infected without showing clinical signs of borna disease (BD), whereas the rats suffered from acute BD. Among 19 horses examined, five were positive for viral RNA in the blood. In a flock of sheep with a history of BD, 1 out of 25 clinically healthy animals was positive. BDV RNA was also detected in cells of the peripheral blood of 10 out of 27 selected humans with psychiatric disorders, and in 2 out of 13 healthy individuals. Remarkably, BDV-specific RNA was present in some cases in the absence of BDV-specific antibodies. Sequence analysis of PCR products confirmed the specificity of the amplification system. The presence of BDV RNA in the blood of naturally and experimentally BDV-infected individuals may point to an incidental but relevant role of blood for the spread of BDV in the infected organism, as well as for the transmission of BDV to other individuals." [Abstract]

Solbrig MV, Koob GF, Fallon JH, Reid S, Lipkin WI.
Prefrontal cortex dysfunction in Borna disease virus (BDV)--infected rats.
Biol Psychiatry. 1996 Oct 1;40(7):629-36.
"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." [Abstract]

Solbrig MV, Koob GF, Joyce JN, Lipkin WI.
A neural substrate of hyperactivity in borna disease: changes in brain dopamine receptors.
Virology. 1996 Aug 15;222(2):332-8.
"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." [Abstract]

Czygan M, Hallensleben W, Hofer M, Pollak S, Sauder C, Bilzer T, Blumcke I, Riederer P, Bogerts B, Falkai P, Schwarz MJ, Masliah E, Staeheli P, Hufert FT, Lieb K.
Borna disease virus in human brains with a rare form of hippocampal degeneration but not in brains of patients with common neuropsychiatric disorders.
J Infect Dis. 1999 Nov;180(5):1695-9.
"To estimate the frequency of persistent Borna disease virus (BDV) infections of the human central nervous system and to determine which neuropsychiatric disorders might be associated with this viral infection, reverse transcription-nested polymerase chain reaction was used to screen a large collection of autopsy brain samples for the presence of BDV-specific nucleic acids. The presence of BDV RNA was found in 3 brains of persons with psychiatric symptoms and prominent hippocampal degeneration previously reported to be positive by others. However, no BDV RNA was detected in 86 randomly collected brains from persons with various psychiatric disorders, including schizophrenia, affective disorders, and Alzheimer's disease, or from suicide victims or in 52 brains from healthy controls. Furthermore, no BDV-RNA was detected in 16 surgical brain samples from persons with epilepsy-associated hippocampal sclerosis. These results indicate that life-long persistent BDV infections are rare in humans and that such infections may be associated with certain forms of hippocampal degeneration." [Abstract]

Solbrig MV, Koob GF, Lipkin WI.
Key role for enkephalinergic tone in cortico-striatal-thalamic function.
Eur J Neurosci. 2002 Nov;16(9):1819-22.
"Whereas the role of dopaminergic tone in the cortico-striatal-thalamic system is well-established, the role of endogenous opioids in the function of this system is less understood. We show that Borna disease virus infection of adult rats results in an increase in preproenkephalin transcripts in the striatum of Borna-infected rats, a region important for forming coordinated sequential motor actions and in developing programmes of thought and motivation. Stereotypic behaviours and dyskinesias, the clinical hallmarks of infection in adult Lewis rats (BD rats), are accompanied by a disrupted pattern of immediate early gene c-fos activation in the motor thalamus, with significance for the breakdown in coordinated sequential motor actions. We also find increased preproenkephalin in infected cultured neuroblastoma and rat foetal glial cells. The expression pattern of enkephalin mRNA in vivo and in vitro suggest that increased enkephalin function is one of the neuropharmacological means by which Borna disease virus causes motor disease of animals and possibly cognitive and affective disease in man, and further suggest that enkephalins play a critical role in the maintenance of a balanced tone of activity in the cortico-basal ganglia-thalamo-cortical loops." [Abstract]

Pletnikov MV, Rubin SA, Schwartz GJ, Moran TH, Sobotka TJ, Carbone KM.
Persistent neonatal Borna disease virus (BDV) infection of the brain causes chronic emotional abnormalities in adult rats.
Physiol Behav. 1999 Jul;66(5):823-31.
"Neonatal Borna disease virus (BDV) brain infection results in selective developmental damage to the hippocampal dentate gyrus and the cerebellum. When mature, neonatally BDV-infected rats show extreme locomotor hyperactivity and reduced freezing behavior in novel environments. Traditional interpretation of both of these behavioral abnormalities would suggest decreased anxiety in infected rats compared to normal animals. However, it also possible that the locomotor hyperactivity in infected rats reflects higher rather than reduced anxiety, and is the result of increased escape responses to aversive stimuli. The present experiments were undertaken to test a hypothesis about elevated anxiety in neonatally BDV-infected adult Lewis rats by studying their species-specific fear-related responses. Compared to normal subjects, BDV-infected rats exhibited locomotor hyperactivity and elevated defecation in a highly aversive, brightly lit open field. As expected, in a less aversive, dimly lit open field, uninfected controls increased ambulation, whereas infected rats significantly decreased locomotor activity and defecation. Unlike uninfected rats, BDV-infected rats exhibited an attenuated freezing response immediately after loud auditory stimuli. On the contrary, immediate freezing responses following footshock were comparable in the two groups of animals indicating an intact ability to freeze in BDV-infected rats. Despite a decreased baseline startle responsiveness, BDV-infected rats demonstrated increased sensitization of the startle response by preceding footshocks, suggesting a tendency toward elevated escape responses. Compared to normal subjects, BDV-infected rats showed decreased conditional freezing and elevated conditional defecation response in the context previously paired with aversive stimulation indicating sparing of an autonomic component of fear conditioning. The findings indicate that neonatally BDV-infected adult rats are hyperreactive to aversive stimuli, possibly as a result of chronic emotional abnormalities." [Abstract]

Takahashi H, Nakaya T, Nakamura Y, Asahi S, Onishi Y, Ikebuchi K, Takahashi TA, Katoh T, Sekiguchi S, Takazawa M, Tanaka H, Ikuta K.
Higher prevalence of Borna disease virus infection in blood donors living near thoroughbred horse farms.
J Med Virol. 1997 Jul;52(3):330-5.
"It is believed that Borna disease virus (BDV), an etiological agent of progressive polioencephalomyelitis in horses and sheep, is closely associated with psychiatric disorders in humans since the prevalence of BDV is higher in psychiatric patients than in blood donors. We investigated whether or not BDVs in humans are derived from infected domestic animals, by characterizing the BDVs in blood donors and horses derived from the same region of Hokkaido island, Japan. The seroprevalences (2.6 to 14.8%) of BDV were significantly higher in the blood donors from four regions where most horse farms are concentrated, compared with only 1% in the blood donors from Sapporo, the largest city in Hokkaido.BDV RNA was also detected in peripheral blood mononuclear cells from most of the seropositive horses and blood donors by nested reverse transcriptase-polymerase chain reaction. These findings support that BDV may be horizontally transmitted, at least in part, from infected horses to humans." [Abstract]

Staeheli, Peter, Sauder, Christian, Hausmann, Jurgen, Ehrensperger, Felix, Schwemmle, Martin
Epidemiology of Borna disease virus
J Gen Virol 2000 81: 2123-2135 [Full Text]

Nakaya T, Kuratsune H, Kitani T, Ikuta K.
[Demonstration on Borna disease virus in patients with chronic fatigue syndrome]
Nippon Rinsho. 1997 Nov;55(11):3064-71.
"Chronic fatigue syndrome (CFS), a recently named heterogeneous disorder, is an illness of unknown etiology. The association between CFS and several viral infection has been suggested. Here, we centered on the possible link between CFS and Borna disease virus (BDV) infection. BDV is a neurotropic, nonsegmented negative-strand (NNS) RNA virus. Recent epidemiological data have suggested that BDV may be closely associated with depression and schizophrenia in humans. In Japanese patients with CFS, the prevalence of BDV infection was 34% (30/89) and 12% (7/57) by immunoblotting and PCR analysis, respectively. Furthermore, anti-BDV antibodies and BDV RNA were detected in a family cluster with CFS. These results suggested that this virus contributes to or initiates CFS, although the single etiologic role of BDV is unlikely." [Abstract]

Evengard B, Briese T, Lindh G, Lee S, Lipkin WI.
Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome.
J Neurovirol. 1999 Oct;5(5):495-9.
"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." [Abstract]

Nakaya T, Takahashi H, Nakamura Y, Asahi S, Tobiume M, Kuratsune H, Kitani T, Yamanishi K, Ikuta K.
Demonstration of Borna disease virus RNA in peripheral blood mononuclear cells derived from Japanese patients with chronic fatigue syndrome.
FEBS Lett. 1996 Jan 8;378(2):145-9.
"CFS, a recently named heterogeneous disorder, is an illness of unknown etiology. The association of CFS with viral infections has been suggested. A common association between CFS and several viruses examined has not been confirmed. Here, we centered on the possible link between CFS and BDV infection. By nested RT-PCR followed by hybridization, BDV RNA was demonstrated as a clear signal in PBMCs in 3 out of 25 CFS patients. The amplified cDNA fragments were cloned and sequenced. A total of 16 clones were studied. Intra-patients divergencies of the p24 were 2-9%, 3-20%, and 3-11% in the deduced amino acids. Inter-patient divergencies among the 16 clones were 3-24%. Antibodies to recombinant BDV p24 protein were detected in 6 CFS patients including one carrying BDV RNA. Overall, these gave the prevalence of 32% (8/25) in Japanese CFS patients, suggesting that Japanese CFS is highly associated with active infection of BDV, or a related agent." [Abstract]

Nakaya T, Takahashi H, Nakamur Y, Kuratsune H, Kitani T, Machii T, Yamanishi K, Ikuta K.
Borna disease virus infection in two family clusters of patients with chronic fatigue syndrome.
Microbiol Immunol. 1999;43(7):679-89.
"A high rate of Borna disease virus (BDV) infection has been demonstrated in patients with chronic fatigue syndrome (CFS). Herein, we focused on BDV infection in two family clusters of patients with CFS: a father, mother, two sons and one daughter (family #1); and a father, mother, two daughters and one son (family #2). All members, except for the elder son in family #1 and the father and son in family #2, were diagnosed with CFS. The results supported that all the family members with CFS were infected with BDV, as evidenced by the presence of antibodies to viral p40, p24 and/or gp18 and BDV p24 RNA in peripheral blood mononuclear cells. The healthy members, except for the father of family #2 who was positive for antibody to p24, were all negative by both assays. Follow-up studies in family #1 continued to reveal BDV antibodies and BDV RNA, except in the mother, who lost the RNA upon slight recovery from the disease." [Abstract]

Wittrup IH, Christensen LS, Jensen B, Danneskiold-Samsee B, Bliddal H, Wiik A.
Search for Borna disease virus in Danish fibromyalgia patients.
Scand J Rheumatol. 2000;29(6):387-90.
"OBJECTIVE: The purpose of this study was to look for Borna disease virus (BDV) in 18 patients with acute onset of fibromyalgia (FMS) following a "flu-like" episode. BDV is a neurotropic RNA virus affecting horses and sheep. Infections in animals have been reported to cause immune mediated disease characterized by abnormalities in behavior. A possible link between BDV and neuropsychiatric diseases in man has been described, and lately a connection to chronic fatigue syndrome (CFS) has been suggested. METHODS: A BDV-specific nested PCR (RT-PCR) was performed on serum and spinal fluid. RESULTS: The BDV genome was not detected in any of the FMS cases. CONCLUSION: Although BDV was not demonstrated in spinal fluid or serum from the tested patients with FMS, we believe that it is important to report our results, since FMS can exhibit many manifestations in common with CFS. Possible reasons for the discrepant findings are discussed." [Abstract]

Fukuda, Koji, Takahashi, Kazuo, Iwata, Yasuhide, Mori, Norio, Gonda, Kenji, Ogawa, Tsuguhiro, Osonoe, Kouichi, Sato, Minako, Ogata, Shin-ichi, Horimoto, Taisuke, Sawada, Takashi, Tashiro, Masato, Yamaguchi, Kazunari, Niwa, Shin-ichi, Shigeta, Shiro
Immunological and PCR Analyses for Borna Disease Virus in Psychiatric Patients and Blood Donors in Japan
J. Clin. Microbiol. 2001 39: 419-429
"The involvement of Borna disease virus (BDV) in psychiatric diseases in humans remains controversial. T-cell memory response and seroprevalence of BDV in patients with psychiatric disorders and blood donors in Japan were evaluated collectively by Western blot (WB) analysis with inhibition test, electrochemiluminescence immunoassay, immunofluorescence assay, and T-cell proliferative response as well as detection of BDV p24 RNA in peripheral blood mononuclear cells (PBMCs). Positive proliferative responses to both BDV p40 and p24 proteins were detected in 9% of patients with mood disorders (4 of 45), 4% of schizophrenic patients (2 of 45), and 2% of blood donors (1 of 45). By WB analysis, the antibody to BDV p40 was detected only in 2% of patients with mood disorders (1 of 45). The BDV p24 antibody was detected in 2% of patients with mood disorders (1 of 45) and 9% of schizophrenic patients. (4 of 45) No plasma reacted with both BDV proteins. The finding of a lower seroprevalence than previously reported suggests the presence of false-positive cases in the previous report. BDV RNA was detected only in 2% of patients with mood disorders (1 of 45). In these three serological assays, T-cell responses, and PCR analysis, there was no significant difference in the prevalence among the three groups. However, we found three psychiatric patients who were positive for both BDV antibodies and T-cell proliferative responses and one patient who was positive for BDV RNA in PBMCs. These findings suggest the usefulness of the proliferative T-cell response and that certain individuals are infected with BDV or a BDV-related virus." [Full Text]

Yamaguchi, Kazunari, Sawada, Takashi, Naraki, Tohru, Igata-Yi, Ruriko, Shiraki, Hiroshi, Horii, Yoichiro, Ishii, Toshinori, Ikeda, Kazuhiko, Asou, Norio, Okabe, Hiroaki, Mochizuki, Manabu, Takahashi, Kazuo, Yamada, Shogo, Kubo, Kaori, Yashiki, Shinji, Waltrip, Royce W., II, Carbone, Kathryn M.
Detection of Borna Disease Virus-Reactive Antibodies from Patients with Psychiatric Disorders and from Horses by Electrochemiluminescence Immunoassay
Clin. Diagn. Lab. Immunol. 1999 6: 696-700
"The prevalence of Borna disease virus (BDV)-specific antibodies among patients with psychiatric disorders and healthy individuals has varied in several reports using several different serological assay methods. A reliable and specific method for anti-BDV antibodies needs to be developed to clarify the pathological significance of BDV infections in humans. We developed a new electrochemiluminescence immunoassay (ECLIA) for the antibody to BDV that uses two recombinant proteins of BDV, p40 and p24 (full length). Using this ECLIA, we examined 3,476 serum samples from humans with various diseases and 917 sera from blood donors in Japan for the presence of anti-BDV antibodies. By ECLIA, 26 (3.08%) of 845 schizophrenia patients and 9 (3.59%) of 251 patients with mood disorders were seropositive for BDV. Among 323 patients with other psychiatric diseases, 114 with neurological diseases, 75 with chronic fatigue syndrome, 85 human immunodeficiency virus-infected patients, 50 with autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosis and 17 with leprosy, there was no positive case except one case each with alcohol addiction, AIDS, and dementia. Although 19 (1.36%) of 1,393 patients with various ocular diseases, 10 (1.09%) of 917 blood donors, and 3 (4.55%) of 66 multitransfused patients were seropositive for BDV-specific antigen, high levels of seroprevalence in schizophrenia patients and young patients (16 to 59 years old) with mood disorders were statistically significant. The immunoreactivity of seropositive sera could be verified for specificity by blocking with soluble p40 and/or p24 recombinant protein. Anti-p24 antibody was more frequent than p40 antibody in most cases, and in some psychotic patients antibody profiles showed only p40 antibody. Although serum positive for both p40 and p24 antibodies was not found in this study, the p40 ECLIA count in schizophrenia patients was higher than that of blood donors. Furthermore, we examined 90 sera from Japanese feral horses. Antibody profiles of control human samples are similar to that of naturally BDV-infected feral horses. We concluded that BDV infection was associated in some way with psychiatric disorders." [Full Text]

Terayama H, Nishino Y, Kishi M, Ikuta K, Itoh M, Iwahashi K.
Detection of anti-Borna Disease Virus (BDV) antibodies from patients with schizophrenia and mood disorders in Japan.
Psychiatry Res. 2003 Sep 30;120(2):201-6.
"The relationship between infection with the Borna Disease Virus (BDV) and the clinical symptoms of schizophrenia and mood disorders (DMS-IV) was investigated. Western blotting techniques were used to examine anti-p10-BDV antibodies in serum from 32 patients with schizophrenia and 33 patients with mood disorders in Japan. The results showed that 1 out of 25 controls (4.0%), 7 out of 32 patients with schizophrenia (21.9%) and 9 out of 33 patients with mood disorders (27.3%) were positive for anti-BDV-p10 antibodies. Compared with levels of anti-BDV-p10 antibodies in controls, the production of anti-BDV-p10 antibodies failed to show a statistically significant relationship with schizophrenia but did show a significant relationship with mood disorder. The subgroup of schizophrenia patients with positive syndromes had a non-significantly higher frequency of anti-BDV-p10 antibodies than the subgroup of patients with negative syndromes. Similarly, the production of anti-BDV-p10 antibodies was non-significantly higher among patients with the unipolar subtype of mood disorder than in those with the bipolar subtype." [Abstract]

Dietrich DE, Bode L, Spannhuth CW, Lau T, Huber TJ, Brodhun B, Ludwig H, Emrich HM.
Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial.
Bipolar Disord. 2000 Mar;2(1):65-70.
"OBJECTIVE: Originally introduced into pharmacotherapy as an antiviral compound, amantadine was shown to also have multiple pharmacological eftfects on the central nervous system. In addition. only a few studies reported on certain antidepressive properties of amantadine. This effect was highlighted by the discovery of its antiviral effect on Borna disease virus (BDV), which is hypothesized to be an etiopathogenetic factor to subtypes of affective disorders. Therefore, the therapeutical use of amantadine in BDV-infected depressive patients was investigated. METHODS: In this open trial, amantadine was added to antidepressive and or mood-stabilizing compounds treating BDV-infected depressed patients (n = 25) with bipolar or major depressive disorders. Amantadine was given twice a day (100-300 mg/day) for a mean of 11 weeks. Antidepressive treatment response was measured on the Hamilton rating scale for depression (HAM-D) and/or with an operationalized diagnostic criteria system (OPCRIT: version 3.31). Virological response was measured by expression of BDV infection parameters in blood samples. RESULTS: The overall response rate of the amantadine augmentation in the BDV-infected patients with regard to depressive symptoms was 68% after a mean of 2.9 weeks of treatment. Bipolar I patients improved faster and did not show any following hypomania. In addition, the decrease of depression tended to correspond with the decrease in viral activity. CONCLUSION: Amantadine appears to show a remarkable antidepressive efficacy in BDV-infected depressive patients. The antidepressive effect in this open trial appeared to be comparable to standard antidepressives, possibly being a result of its antiviral effect against BDV as a potentially relevant etiopathogenetic factor in these disorders." [Abstract]

Ferszt R, Kuhl KP, Bode L, Severus EW, Winzer B, Berghofer A, Beelitz G, Brodhun B, Muller-Oerlinghausen B, Ludwig H.
Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection.
Pharmacopsychiatry. 1999 Jul;32(4):142-7.
"Amantadinesulfate is a well known substance which has proven useful in the treatment and prophylaxis of viral infections, in treating symptoms of Parkinson's disease, cocaine dependence, and apathy in multiple sclerosis. It has also been reported as having mild antidepressive effects not sufficient to warrant its use as an antidepressant. Striking antidepressive effects in some patients have been attributed to its antiviral activity against human Borna disease virus (BDV) infection which is frequently seen in patients with depressive episodes. In this 8 to 12 week open study of oral amantadine in 30 depressed patients with various states of BDV infection we found a significant antidepressive response in 19 of 30. Peripheral BDV antigen indicating acute infection was cleared in both responders and non-responders, but only in responders peripheral infection was significantly reduced." [Abstract]

Dietrich DE, Kleinschmidt A, Hauser U, Schneider U, Spannhuth CW, Kipp K, Huber TJ, Wieringa BM, Emrich HM, Johannes S.
Word recognition memory before and after successful treatment of depression.
Pharmacopsychiatry. 2000 Nov;33(6):221-8.
"One of the most frequent and neuropsychologically well investigated symptoms in depression is reduced memory capacity. In this study, we investigated the course of disease in 16 patients with moderate depression and Borna disease virus (BDV) infection. Recently, it could be shown that BDV infection might play an important role in the etiology of subtypes of depression. Amantadine treatment was used as an antidepressant and antiviral compound. In order to assess memory capacity, event-related potentials (ERPs) were evaluated in ten of sixteen patients in a continuous word recognition experiment using a series of emotionally neutral, positive or negative words. During the treatment period the patients' clinical condition improved significantly. ERPs showed a reduced old/new effect before and after treatment independent of the words' emotional content. These findings suggest a reduced memory capacity being relatively independent of clinical outcome and ability to use emotional connotations for memory mechanisms. However, a significant positive shift over frontal electrodes did occur, which was concomitant with the improvement of depression, suggesting evidence for changed frontal cortical activity." [Abstract]

Huber TJ, Dietrich DE, Emrich HM.
Possible use of amantadine in depression.
Pharmacopsychiatry. 1999 Mar;32(2):47-55.
"Amantadine, originally used in the treatment and prophylaxis of influenza infection, has also proved beneficial in drug-induced Parkinsonism, Parkinson's disease, traumatic head injury, dementia, multiple sclerosis and cocaine withdrawal. Amantadine appears to act through several pharmacological mechanisms, none of which has been identified as the one chief mode of action. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels. However, it is still uncertain which of these actions are relevant in therapeutic doses. One new aspect is the antiviral effect of amantadine on Borna disease virus, which it is suspected may possibly play a role in affective disorders. All of these actions could constitute an antidepressant property, and it is suggested that amantadine might work as an antidepressant not through one, but through several mechanisms thought to be related to antidepressant activity. Effects of amantadine on symptoms of affective disorders have been demonstrated in several trials administering it for varying purposes. Additionally, animal studies as well as clinical trials in humans have hinted at an antidepressant activity of amantadine. We present here an overview of the current data. However, only a limited body of evidence is available, and further studies are needed to investigate the efficacy of amantadine as well as its modes of action in depression." [Abstract]

Ferszt R, Severus E, Bode L, Brehm M, Kuhl K-P, Berzewski H, Ludwig H.
Activated Borna disease virus in affective disorders.
Pharmacopsychiatry. 1999 May;32(3):93-8.
"BACKGROUND: Borna disease virus (BDV) is an animal pathogen that causes behavioral changes in animals. Previous studies have found a high prevalence of serum antibodies as well as Borna disease viral antigens (BDVAGs) and RNA in the white blood cells of psychiatric patients, especially those with affective disorders. The present study attempts to offer a better description of the BDVAG cohort using clinical parameters. METHODS: The prevalence of BDVAG was examined in the peripheral mononuclear leukocytes of patients with a major depressive episode. A subgroup of patients underwent further clinical analysis. RESULTS: In this pilot study, at least, there was a significant difference in the prevalence of BDVAG between psychiatric inpatients with a major depressive episode and control individuals. It also appeared that BDVAG is more frequent in patients with recurrent major depression or bipolar disorder than in those with any other psychiatric disorder studied. The number of previous depressive episodes, as well as symptoms involving fatigue and concentration difficulties were positively related to BDVAG. CONCLUSIONS: The high rate of BDVAG, especially in fatigued patients with recurrent major depression or bipolar disorder, may be a nonspecific aspect of immunosuppression. The question remains whether this neurotropic virus may contribute to the pathogenesis of some types of affective disorder." [Abstract]

Bode L, Ferszt R, Czech G.
Borna disease virus infection and affective disorders in man.
Arch Virol Suppl. 1993;7:159-67.
"Borna Disease virus (BDV) can persistently infect the central nervous system of a broad spectrum of animal species. The clinical course varies from slight behavioral disturbances to a fatal neurological syndrome. In-vivo diagnosis is based on the strong humoral immune response to BDV antigens. Since also human infections could be confirmed by specific antibodies and increased seroprevalence was found in patients with chronic neurologic or immunologic disorders, the contribution of BDV or a BDV-like human variant to syndromes with yet unknown etiology became of great interest. We presented the first data of a current follow-up study on 70 psychiatric patients who were tested three times each after hospitalization. In contrast to previously found low prevalence of antibody carriers by screening (2-4%), we now found 20% positives by follow-up testing. Furthermore, of the randomly selected patients with different psychiatric diagnosis, the highest proportion of antibody carriers was detected among patients with major depression (more than 30%), compared to only 8% among patients with dysthymia (neurotic depression). This led us to hypothesize that Bornavirus infection might contribute somehow to the syndrome of major depressive illness by altering neuronal cells in the limbic system." [Abstract]

Rott R, Herzog S, Bechter K, Frese K.
Borna disease, a possible hazard for man?
Arch Virol. 1991;118(3-4):143-9.
"Evidence is presented that Borna disease (BD) virus, which is known to cause encephalopathy in horses, sheep, and a broad range of experimental animals, or a related agent, can infect man and may induce mental disorders. BD virus-specific antibodies could be demonstrated in 4-7% of sera (depending on origin) from more than 5000 psychiatric or neurological patients from Germany, U.S.A. and Japan. Antibodies from seropositive patients reacted with a BD virus-specific protein translated by RNAs which were transcribed from a cDNA clone obtained from BD virus-infected tissues. When the cerebrospinal fluid from three seropositive patients was inoculated into rabbits or rabbit embryonic brain cell cultures, evidence was obtained that suggests the presence of BD virus or a related agent." [Abstract]

Rott R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W, Koprowski H.
Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders.
Science. 1985 May 10;228(4700):755-6.
"Borna disease virus causes a rare meningoencephalitis in horses and sheep and has been shown to produce behavioral effects in some species. The possibility that the Borna virus is associated with mental disorders in humans was evaluated by examining serum samples from 979 psychiatric patients and 200 normal volunteers for the presence of Borna virus-specific antibodies. Antibodies were detected by the indirect immunofluorescence focus assay. Antibodies to the virus were demonstrated in 16 of the patients but none of the normal volunteers. The patients with the positive serum samples were characterized by having histories of affective disorders, particularly of a cyclic nature. Further studies are needed to define the possible involvement of Borna virus in human psychiatric disturbances." [Abstract]

Amsterdam JD, Winokur A, Dyson W, Herzog S, Gonzalez F, Rott R, Koprowski H.
Borna disease virus. A possible etiologic factor in human affective disorders?
Arch Gen Psychiatry. 1985 Nov;42(11):1093-6.
"Borna disease virus is a unique neurotropic agent that appears to have a predilection for the limbic area of the brain. In some animal species, it can produce a behavioral syndrome characterized by aggressive and passive phases. This syndrome has suggested an analogy to certain human affective disorders. In this preliminary study, we examined the possible involvement of Borna disease virus in the etiology of human mood disorders by assaying for virus-specific antibodies in 265 patients with unipolar or bipolar depression and 105 normal, healthy volunteers. Twelve patients (4.5%) and none of the healthy controls demonstrated this antibody in their serum samples. It will be necessary to replicate and extend these intriguing preliminary results to determine if Borna disease virus is possibly involved in the pathogenesis of affective disorders in humans." [Abstract]

Fu ZF, Amsterdam JD, Kao M, Shankar V, Koprowski H, Dietzschold B.
Detection of Borna disease virus-reactive antibodies from patients with affective disorders by western immunoblot technique.
J Affect Disord. 1993 Jan;27(1):61-8.
"Borna disease (BD) virus is a partially characterized neurotropic agent with a predilection for neurons and astrocytes in the limbic system and cerebrum of infected hosts. Although it usually causes a fatal encephalitis, some laboratory animals which have been experimentally inoculated can develop a persistent non-fatal infection characterized by a neuro-behavioral syndrome akin to human manic-depression. Using immunofluorescent techniques, we previously observed BD virus-specific antibodies in the sera of 4.5% of affectively ill patients, with the highest titers present in bipolar patients. More recently, we have developed a sensitive Western blot assay for the detection of anti-BD virus antibodies to a 38/40 kDa and 24 kDa protein in human serum. In the present study, we screened 138 affectively ill patients and 117 healthy controls and observed a significantly great proportion of patients with antibodies to the 38/40 kDa protein (P < 0.0001), the 24 kDa protein (P < 0.05) and both the 38/40 kDa and 24 kDa proteins (P < 0.025). These data extend prior reports on the presence of BD virus-specific antibodies in psychiatric patients, and suggest that a BD virus-like agent may be associated with affective illness in humans." [Abstract]

Chen CH, Chiu YL, Wei FC, Koong FJ, Liu HC, Shaw CK, Hwu HG, Hsiao KJ.
High seroprevalence of Borna virus infection in schizophrenic patients, family members and mental health workers in Taiwan.
Mol Psychiatry. 1999 Jan;4(1):33-8.
"Borna disease virus (BDV), a negative-strand RNA virus, has been reported to be associated with severe psychiatric disorders. The association is mainly based on the findings that patients with schizophrenia and depression have a higher seroprevalence rate of BDV-specific antibodies than controls. In addition, psychiatric patients were also found to have a higher detection rate of BDV transcripts in their blood than controls. By using an improved Western blot analysis, we first demonstrated that Chinese schizophrenic patients from Taiwan also have a higher seroprevalence of BDV-specific antibodies than controls (12.1% vs 2.9%, P< 0.001), providing support to the positive association between BDV and psychiatric disorders in our population. Because of the contagious nature of viral infection, we further examined patients' family members and mental health workers, who have close contact with patients. We found that both groups also have a higher seroprevalence of BDV-specific antibodies, 12.1% and 9.8%, respectively, than controls. This finding provides some evidence for a possible human-to-human transmission of Borna disease virus. Our finding needs further independent verification from other research groups and the clinical relevance of this preliminary observation deserves further study." [Abstract]

Iwata, Yasuhide, Takahashi, Kazuo, Peng, Xie, Fukuda, Koji, Ohno, Koei, Ogawa, Tsuguhiro, Gonda, Kenji, Mori, Norio, Niwa, Shin-ichi, Shigeta, Shiro
Detection and Sequence Analysis of Borna Disease Virus p24 RNA from Peripheral Blood Mononuclear Cells of Patients with Mood Disorders or Schizophrenia and of Blood Donors
J. Virol. 1998 72: 10044-10049
"Borna disease virus (BDV) p24 RNA was detected in the peripheral blood mononuclear cells (PBMCs) of psychiatric patients and blood donors by nested reverse transcriptase PCR (RT-PCR). The prevalences of BDV p24 RNA in patients with mood disorders (4%) and schizophrenia (4%) were not significantly different from that in blood donors (2%). This finding was inconsistent with previous reports that showed either a high prevalence or absence of BDV p24 RNA in patients with psychiatric disorders. The differences in BDV p24 RNA prevalence in these studies may be due to differences in the criteria for positivity, the number of PBMCs used for RNA extraction, or the amount of RNA tested for nested RT-PCR or to laboratory contamination. Sequence analysis of BDV p24 RNA from the PBMCs of patients and blood donors showed a high nucleotide sequence conservation but definite nucleotide mutations compared with horse BDV p24 RNA sequences. In comparison with human BDV p24 RNA sequences previously reported from Japan and Germany, there were several positions with silent nucleotide mutations among these clones." [Full Text]

Yang AY, Zhang FM, Li JH, Li GM, Ma PL, Gu HX, Ikuta K.
[Detection of Borna disease virus-p24 specific antibody in the sera of schizophrenic patients of China by means of Western-blot]
Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2003 Mar;17(1):85-7.
"BACKGROUND: To investigate whether Borna disease virus (BDV) infection is related to the schizophrenic patients from China. METHODS: A reliable Western-blot method for detection of BDV-p24 antibody was established by adjusting the reaction conditions of BDV-p24 recombinant protein and specific antibodies. The sera of schizophrenic patients and normal controls from Heilongjiang Province were screened for specific BDV-p24 antibody by this method, and the BDV-p24 antibody positive sera were confirmed by the Western-blot method with sera-GST protein absorption. RESULTS: Ten of 116 (8.6%) schizophrenic patients were found to be positive for BDV-p24 specific antibody, while no BDV-p24 specific antibody was found in sera of normal controls. CONCLUSIONS: The results demonstrate that the Borna disease virus infection also exists in China, and the infection is possibly associated with schizophrenia in some way." [Abstract]

Sauder, C, Muller, A, Cubitt, B, Mayer, J, Steinmetz, J, Trabert, W, Ziegler, B, Wanke, K, Mueller-Lantzsch, N, de la Torre, JC, Grasser, FA
Detection of Borna disease virus (BDV) antibodies and BDV RNA in psychiatric patients: evidence for high sequence conservation of human blood-derived BDV RNA
J. Virol. 1996 70: 7713-7724
"In several vertebrate species, Borna disease virus (BDV), the prototype of a new group of animal viruses, causes central nervous system disease accompanied by diverse behavioral abnormalities. Seroepidemiological data indicate that BDV may contribute to the pathophysiology of certain human mental disorders. This hypothesis is further supported by the detection of both BDV antigens and BDV RNA in peripheral blood mononuclear cells (PBMCs) of patients with psychiatric disorders and the isolation of BDV from such PBMCs. Here we describe serological and molecular epidemiological studies on psychiatric patients and healthy individuals from the area of Homburg, Germany. Using a novel Western blot (immunoblot) assay, we found a BDV seroprevalence of 9.6% among 416 neuropsychiatric patients, which is significantly higher than the 1.4% found among 203 healthy control individuals. Human sera displayed a prominent immunoreactivity against the virus nucleoprotein, the p40 antigen. Reverse transcriptase-mediated PCR analysis of RNA extracted from PBMCs of a subset of 26 of the neuropsychiatric patients revealed that 50% were BDV RNA positive. Three of the 13 BDV RNA-positive patients also had BDV-positive serology, whereas one patient with serum antibodies to BDV p40 antigen did not harbor detectable BDV RNA in PBMCs. BDV p40 and p24 sequences derived from human PBMCs exhibited both a high degree of inter- and intrapatient conservation and a close genetic relationship to animal-derived BDV sequences." [Abstract/Full Text]

Iwahashi K, Watanabe M, Nakamura K, Suwaki H, Nakaya T, Nakamura Y, Takahashi H, Ikuta K.
Positive and negative syndromes, and Borna disease virus infection in schizophrenia.
Neuropsychobiology. 1998;37(2):59-64.
"The relationship between Borna disease virus (BDV) infection and positive and negative syndromes in schizophrenia was investigated. By nested RT-PCR and Western blotting, BDV-specific RNA and anti-BDV antibodies were examined in blood from 67 schizophrenic patients (DSM-III-R) in Japan, and the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) were analyzed. There were significant (p < 0.05) differences in the composite index denoting the positive minus negative difference indicating a dominant contribution by negative items, and the proportion of negative type (positive minus negative value below zero) patients, between patients positive and negative for anti-BDV p24 antibodies. It is possible that BDV infection with induction of BDV p24 antibodies may be associated with negative syndromes in schizophrenic patients." [Abstract]

Waltrip RW 2nd, Buchanan RW, Carpenter WT Jr, Kirkpatrick B, Summerfelt A, Breier A, Rubin SA, Carbone KM.
Borna disease virus antibodies and the deficit syndrome of schizophrenia.
Schizophr Res. 1997 Feb 28;23(3):253-7.
"We detected anti-Borna disease virus (BDV) antibodies at a 14.4% rate in patients with schizophrenia. The hypothesis of a higher rate of BDV seropositivity in deficit syndrome was borne out in a subset of 64 patients categorized according to the Schedule for the Deficit Syndrome with 5/15 seropositive deficit and 4/49 seropositive nondeficit (p < 0.05). This suggests that the antibodies and possibly a BDV-like virus are pathogenetically linked to this form of schizophrenia." [Abstract]

Iwahashi K, Watanabe M, Nakamura K, Suwaki H, Nakaya T, Nakamura Y, Takahashi H, Ikuta K.
Clinical investigation of the relationship between Borna disease virus (BDV) infection and schizophrenia in 67 patients in Japan.
Acta Psychiatr Scand. 1997 Dec;96(6):412-5.
"The relationship between Borna disease virus (BDV) infection and schizophrenia in the clinical time course was investigated. By nested reverse-transcribed polymerase chain reaction (RT-PCR) and Western blotting, BDV-specific RNA and anti-BDV antibodies were examined in the EDTA-treated blood from 67 schizophrenic patients (according to DSM-III-R) in Japan. A significantly higher proportion (45%) of anti-BDV antibody and/or BDV RNA carriers were found among these 67 schizophrenic patients than in 26 controls (0%). There were no apparent associations of BDV infection with age, age at onset, period of hospitalization, accompanying somatic diseases, a past history of tuberculosis, a history of transfusion, a family history, or doses of psychotropic drugs. It is possible that, at least, BDV infection in schizophrenic patients may not be a nosocomial (hospital-acquired) infection, although the route of BDV infection in humans remains unidentified. More studies on the relationship between BDV infection and clinical psychosomatic features should be performed in order to elucidate the pathogenesis of schizophrenia." [Abstract]

Waltrip RW 2nd, Buchanan RW, Summerfelt A, Breier A, Carpenter WT Jr, Bryant NL, Rubin SA, Carbone KM.
Borna disease virus and schizophrenia.
Psychiatry Res. 1995 Jan 31;56(1):33-44.
"The development of a new serological assay method to detect antibodies in human sera recognizing Borna disease virus (BDV) proteins and a clinical pilot study are presented. Psychiatric patients from a schizophrenia research clinic in Baltimore, Maryland, were examined for antibodies to BDV antigen with traditional indirect immunofluorescence assays (IFA) that used both single and double labeling techniques and also with a Western blot assay capable of detecting antibodies to the three BDV proteins from a human neuroblastoma cell line. Thirteen of 90 (14.4%) patients and 0/20 control subjects had antibodies that recognized more than one BDV protein on the Western blot. Three patients had antibodies that recognized all three BDV proteins. Magnetic resonance imaging assessments of the volume of the putamen (with controls for total cranial volume) differentiated BDV+ from BDV- patients, and there were trend differences for bilateral amygdalae and the left amygdala-hippocampal process. We conclude that: (1) the Western blot assay is superior to IFA assays in BDV serology studies, (2) detection of antibodies to more than one BDV protein is a useful working criterion for seropositivity, (3) the 14.5 kDa BDV protein is 10 times more predictive of seropositivity than either the 38/40 kDa or the 24 kDa protein, (4) there is tentative evidence for a schizophrenia-control difference in the prevalence of anti-BDV antibodies, and (5) it is likely that there are neuroanatomical/behavioral features that differentiate seropositive from seronegative schizophrenic patients." [Abstract]

Sierra-Honigmann AM, Carbone KM, Yolken RH.
Polymerase chain reaction (PCR) search for viral nucleic acid sequences in schizophrenia.
Br J Psychiatry. 1995 Jan;166(1):55-60.
"BACKGROUND. Previous studies looking for evidence of viral infection in schizophrenics have yielded conflicting results. We searched for viral nucleic acids to test the hypothesis of the viral aetiology of schizophrenia. METHOD. We used the polymerase chain reaction (PCR) to search for cytomegalovirus (CMV), human immunodeficiency virus (HIV), influenza A, Borna disease virus (BDV), and bovine viral diarrhoea virus (BVDV) in: hippocampus from three schizophrenic and three non-schizophrenic subjects; cerebrospinal fluid (CSF) from 48 schizophrenic patients; CSF and peripheral blood mononuclear cells (PBMC) from nine sets of identical twins discordant for schizophrenia; and SK-N-SHEP cells co-cultured with schizophrenic and non-schizophrenic brain homogenates. All patients met DSM-III-R criteria. RESULTS. Virus-specific nucleic acids were not found in any of the samples tested. CONCLUSIONS. The absence of viral nucleic acids in the samples tested suggest that, in these patients, schizophrenia is not associated with a persistent or latent infection due to these viruses." [Abstract]

Planz O, Rziha HJ, Stitz L.
Genetic relationship of Borna disease virus isolates.
Virus Genes. 2003 Jan;26(1):25-30.
"The infection of humans with Boma disease virus (BDV) is still a matter of debate. In a recent publication, we described a BDV (RW98) isolated from the blood of a psychiatric patient. The RNA of this virus differed more than 5% from that of the widely used strain He/80, which was supposed to represent our laboratory virus. Here, we show that the virus used in our laboratory was not He/80 and, furthermore, that RW98 has sequence identity to the laboratory strain. We also present data that BDV-specific nucleic acid detected in blood of the donor of the presumed RW98 isolate and one other patient differs from all known BDV-p24 sequences, arguing for the existence of BDV sequences in man." [Abstract]

Chen CH, Chiu YL, Shaw CK, Tsai MT, Hwang AL, Hsiao KJ.
Detection of Borna disease virus RNA from peripheral blood cells in schizophrenic patients and mental health workers.
Mol Psychiatry. 1999 Nov;4(6):566-71.
"Accumulating evidence suggests that Borna disease virus (BDV), a neurotropic, negative-stranded RNA virus, might be associated with certain human mental disorders. Several research groups reported that psychiatric patients had a significantly higher prevalence of BDV serum antibodies than normal controls. In addition, a significantly higher presence of BDV RNA from peripheral blood cells was identified in mental patients than in controls. In our previous study, we first identified the presence of BDV serum antibodies in a cohort of Chinese schizophrenic patients from Taiwan, and we also demonstrated a significantly higher seroprevalence of BDV antibodies among schizophrenic patients than in non-psychiatric controls. Prompted by the positive seroepidemiological result, we set out to investigate the detection of BDV RNA from the peripheral blood cells of our schizophrenic patients. By using the reverse transcription-polymerase chain reaction (RT-PCR) method, 10 out of 74 Chinese schizophrenic patients from Taiwan were found to have BDV RNA in their blood cells, whereas only one out of 69 controls was positive. The BDV RNA detection rate among schizophrenic patients was significantly higher than that in controls (14% vs 1.4%, P < 0.01). Furthermore, we studied the BDV RNA detection rate among mental health workers, and seven out of 45 mental health workers were found to have positive results. The prevalence rate was significantly higher than that in normal controls (15% vs 1.4%, P < 0.001), which lends further support to our previous finding that mental health workers have a significantly higher presence of BDV serum antibodies. In summary, our data support the finding that BDV infection might be a contributory factor to the pathogenesis of schizophrenia in the Chinese population." [Abstract]

Rybakowski F, Sawada T, Yamaguchi K, Rajewski A, Rybakowski J.
Borna Disease Virus--reactive antibodies in Polish psychiatric patients.
Med Sci Monit. 2002 Sep;8(9):CR642-6.
"BACKGROUND: It has been proposed that the Borna Disease Virus (BDV) plays a role in the etiopathogenesis of psychiatric disorders. We assessed BDV seropositivity in Polish psychiatric patients and healthy controls, and the relationship between seropositivity and selected diagnostic and clinical variables. MATERIAL/METHODS: Serum samples from 946 psychiatric patients with different diagnoses (ICD-10) and 407 psychiatrically healthy controls were assayed. The ECLIA method was used, which enables the assessment of two anti-BDV antibodies: anti-p24 and anti p-40. Data were also collected on diagnosis, age, age at onset, and place of residence. RESULTS: Only anti-p24 antibodies were found. The seropositivity rates were: 2.4% and 1.0%, respectively, in patients and controls (p=0.1). A significant difference between patients and controls was observed in mental retardation and affective-anxiety spectrum disorders. Seropositivity did not show any association with demographic variables, but it was elevated in patients with recent onset of disease vs. remote onset of disease (10.2% vs. 1.6%; p=0.0003). CONCLUSIONS: Significantly higher anti-BDV seropositivity was found in Polish psychiatric patients with affective-anxiety spectrum disorders and mental retardation than in controls. The association between recent onset disorders and higher anti-BDV response, in the light of recent reports on circulating immune complexes of BDV antigens and antibodies, warrants further studies on the longitudinal course of humoral response to BDV." [Abstract]

Rybakowski F, Yamaguchi K, Krzyminski S, Zmyslony F, Biernat J, Kocialkowski M, Tandeck A, Trafarska B, Zalejski M, Sawada T, Naraki T, Czerski P, Rajewski A, Rybakowski JK.
[Detection of anti-Borna disease virus antibodies in patients hospitalized in psychiatric hospitals located in the mid-Western region of Poland]
Psychiatr Pol. 2001 Sep-Oct;35(5):819-29.
"Borna Disease Virus (BDV) is single stranded RNA virus, which may infect a wide range of animal species. Manifestations of the experimental BDV infection show some resemblance to psychopathological symptoms of mental disorders in humans. Several reports suggest the higher prevalence of anti-BDV antibodies in psychiatric patients than in healthy controls. However, the seroprevalence of anti-BDV antibodies varied due to the different serological methods used in the previous studies. Electrochemiluminescence Immunoassay (ECLIA) is a recently developed, highly specific method of detecting antibodies directed toward two BDV proteins: p24 and p40. We used the ECLIA method for the assessment of seropositivity in 946 psychiatric patients hospitalized in the psychiatric hospitals in the western part of Poland. All patients were clinically diagnosed with ICD-10 criteria. Anti-p40 antibodies have not been found in the studied sample. We found anti p-24 antibodies in 23 cases, which give the seroprevalence rate of 2.4%. This result is consistent with the outcome of Japanese population assessment, done with the same methodology. The seropositive cases did not show diagnostic specificity. We did not find statistically significant gender differences in rate of seropositivity. The seroprevalence of anti-BDV antibodies was not significantly different in patients of urban and rural residence, and in patients of different age groups. This is the first demonstration of anti-BDV antibodies in the Polish population of patients hospitalized in psychiatric hospitals." [Abstract]

Selten JP, van Vliet K, Pleyte W, Herzog S, Hoek HW, van Loon AM.
Borna disease virus and schizophrenia in Surinamese immigrants to the Netherlands.
Med Microbiol Immunol (Berl). 2000 Nov;189(2):55-7.
"Borna disease virus (BDV) has been suggested to play a role in the etiology of schizophrenia. We tested the hypothesis that markers of BDV infection are more frequent in Surinamese immigrants to the Netherlands, diagnosed with schizophrenia, than in Dutch-born healthy subjects. For reasons that are poorly understood there is an increased incidence of schizophrenia in this immigrant group. Blood was obtained from 29 male schizophrenic patients (DSM-IV criteria) and from 26 healthy males. For detection of anti-BDV antibodies an indirect immunofluorescence assay (IFA) was performed. A nested, reverse-transcriptase-PCR, using primers specific for the p24 and p40 BDV genes, was used to determine BDV-RNA in peripheral blood mononuclear cells. Contrary to our expectations, the frequencies of BDV markers in the group of healthy subjects, as determined by IFA and both PCRs, exceeded that in the group of patients. The results do not support an association between markers of BDV infection in blood and schizophrenia. It is unlikely that the high incidence of schizophrenia in Surinamese immigrants is caused by BDV, but the small number of subjects examined do not warrant definitive conclusions." [Abstract]

Tsuji K, Toyomasu K, Imamura Y, Maeda H, Toyoda T.
No association of borna disease virus with psychiatric disorders among patients in northern Kyushu, Japan.
J Med Virol. 2000 Jul;61(3):336-40.
"There is controversy over the prevalence of Borna disease virus (BDV) antibodies and its RNA in the peripheral blood mononuclear cells (PBMCs) of psychiatric patients, and the contribution of BDV to human psychiatric disorders. We examined 299 plasma and 229 PBMC samples. No plasma samples were positive for BDV-p40, p24 or gp18 antibodies by western blot analysis. The prevalence of BDV RNA in the psychiatric (schizophrenic) patients (1.8%) was not significantly different from that in the healthy volunteers (0.6%). The nucleotide sequences of BDV p40 and p24 were highly conserved with those of BDV He/80. Our results suggested that there is a lack of association between BDV infection and psychiatric disorders among the patients in Northern Kyushu, Japan." [Abstract]

Kim YK, Kim SH, Choi SH, Ko YH, Kim L, Lee MS, Suh KY, Kwak DI, Song KJ, Lee YJ, Yanagihara R, Song JW.
Failure to demonstrate Borna disease virus genome in peripheral blood mononuclear cells from psychiatric patients in Korea.
J Neurovirol. 1999 Apr;5(2):196-9.
"RNA, extracted from peripheral blood mononuclear cells (PBMC) obtained from 81 Korean psychiatric patients (39 with schizophrenia, 33 with bipolar affective disorders and nine with major depression), was analyzed for a 391-nucleotide, highly conserved region of the p24 protein-encoding ORF II of Borna disease virus (BDV), using nested reverse transcription-polymerase chain reaction (RT-PCR). BDV genomic RNA was not detected in PBMC from any of the 81 Korean psychiatric patients. These data do not support an etiologic association between BDV infection and neuropsychiatric disorders in humans." [Abstract]

Kubo, K, Fujiyoshi, T, Yokoyama, MM, Kamei, K, Richt, JA, Kitze, B, Herzog, S, Takigawa, M, Sonoda, S
Lack of association of Borna disease virus and human T-cell leukemia virus type 1 infections with psychiatric disorders among Japanese patients
Clin. Diagn. Lab. Immunol. 1997 4: 189-194
"Borna disease virus (BDV) infection has been suspected to be a possible etiological factor in human psychiatric disorders and recently in chronic fatigue syndrome. Evidence of the correlation of BDV infection with these disorders remained unclear. Kagoshima is known to be one of the major areas in which human T-cell leukemia virus type 1 (HTLV-1) is endemic; this is the first isolated human retrovirus that causes adult T-cell leukemia with neurological symptoms. The present study aimed to clarify whether BDV and HTLV-1 infections are associated with psychiatric disorders among Japanese patients. Subjects were 346 patients with psychiatric disorders (schizophrenia, 179; mood disorder, 123; and others, 44) and 70 healthy controls. Anti-BDV antibodies from plasma samples were screened by the indirect immunofluorescence (IF) method using BDV-infected MDCK cells. Results revealed that only three samples were found to be weakly positive for BDV in the IF assay and seronegative by Western blot (immunoblot) assay. Furthermore, BDV-p24 related RNA in peripheral blood mononuclear cells from 106 of 346 psychiatric patients and 12 or 70 healthy controls by p24-reverse transcription PCR was examined. Two mood disorder patients were positive for BDV-p24 RNA but seronegative. To detect anti-HTLV-1 antibodies the plasma samples were screened by the particle agglutination method and no significant difference in seropositivity for anti-HTLV-1 antibody was found between the patients and healthy controls. These results also suggested that there is a lack of association between BDV and HTLV-1 infections with psychiatric disorders among Japanese patients." [Abstract/Full Text]

Nowotny, Norbert, Kolodziejek, Jolanta, Jehle, Christian O., Suchy, Angelika, Staeheli, Peter, Schwemmle, Martin
Isolation and Characterization of a New Subtype of Borna Disease Virus
J. Virol. 2000 74: 5655-5658
"Borna disease virus (BDV), the causative agent of severe meningoencephalitis in a wide variety of animal species, has been considered to be genetically invariable and to form a single type within the genus Bornavirus of the family Bornaviridae. BDV infections are of particular interest, because for the first time a virus infection appears to be linked to human psychiatric disorders. We now describe a new subtype of BDV isolated from a horse which was euthanatized due to severe, incurable neurological disease. The nucleotide sequence of this new strain, named No/98, differs from the reference strains by more than 15%, and the subtype is difficult to detect by standard reverse transcriptase PCR protocols. The nucleotide exchanges of the novel BDV isolate have surprisingly little effect on the primary structures of most viral proteins, with the notable exception of the X protein (p10), which is only 81% identical to its counterpart in reference strains. Our data indicate that the genome of BDV is far more variable than previously assumed and that naturally occurring subtypes may escape detection by currently used diagnostic assays."
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Recent Borna Virus Research

1) Bechter K
Updating the mild encephalitis hypothesis of schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jul 3;
Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A 'late hit' and gene-environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within changing environments, although they are associated with the disadvantage of increased susceptibility to psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome phase and the transition to a diseased status may be related to LLNI processes emerging and varying over time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders, which result from three required factors: genes, the environment, and the immune system. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided. A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from reactivation related to persistent infection) may be involved and other pathomechanisms including dysfunction of the blood-brain barrier or the blood-CSF barrier, CNS-endogenous immunity and the volume transmission mode balancing wiring transmission (the latter represented mainly by synaptic transmission, which is often described as being disturbed in schizophrenia). Volume transmission is linked to CSF signaling; and together could represent a common pathogenetic link for the distributed brain dysfunction, dysconnectivity, and brain structural abnormalities observed in schizophrenia. In addition, CSF signaling may extend into peripheral tissues via the CSF outflow pathway along brain nerves and peripheral nerves, and it may explain the peripheral topology of neuronal dysfunctions found, like in olfactory dysfunction, dysautonomia, and even in peripheral tissues, i.e., the muscle lesions that were found in 50% of cases. Modulating factors in schizophrenia, such as stress, hormones, and diet, are also modulating factors in the immune response. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of cases. [PubMed Citation] [Order full text from Infotrieve]

2) Schleife H, Sachtleben C, Finck Barboza C, Singer S, Hinz A
Anxiety, depression, and quality of life in German ambulatory breast cancer patients.
Breast Cancer. 2012 Jun 3;
BACKGROUND: The aim of the study was to determine the predictors of health-related quality of life in ambulatory breast cancer patients. METHODS: A total of 107 breast cancer outpatients were tested with the Hospital Anxiety and Depression Scale (HADS) and the quality of life instrument EORTC QLQ-C30. Furthermore, the degree of social support and shared decision making (SDM) were assessed. RESULTS: In nearly all domains of EORTC QLQ-C30 the patients reported worse mean scores than the general population in a clinically significant range, especially in the symptom scales. Therapy-related factors and the degree of SDM contributed only marginally to quality of life. Social support, however, proved to be predictive of better mental health and better quality of life in many domains. CONCLUSION: Irrespective of the therapy, the social network of the patients should be activated to help the patients to cope with the disease. However, the findings do not support the idea that enhanced SDM would have beneficial effects on mental health. [PubMed Citation] [Order full text from Infotrieve]

3) Hornig M, Briese T, Licinio J, Khabbaz RF, Altshuler LL, Potkin SG, Schwemmle M, Siemetzki U, Mintz J, Honkavuori K, Kraemer HC, Egan MF, Whybrow PC, Bunney WE, Lipkin WI
Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.
Mol Psychiatry. 2012 May;17(5):486-93.
In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

4) Arias I, Sorlozano A, Villegas E, de Dios Luna J, McKenney K, Cervilla J, Gutierrez B, Gutierrez J
Infectious agents associated with schizophrenia: a meta-analysis.
Schizophr Res. 2012 Apr;136(1-3):128-36.
Schizophrenia is a highly disabling and limiting disorder for patients and the possibility that infections by some microorganisms may be associated to its development may allow prevention and recovery. In the current study we have done a meta-analysis of studies that have assessed the possible association between detection of different infectious agents and schizophrenia. We report results that support the idea that there is a statistically significant association between schizophrenia and infection by Human Herpesvirus 2 (OR=1.34; CI 95%: 1.09-1.70; p=0.05), Borna Disease Virus (OR=2.03; CI 95%: 1.35-3.06; p<0.01), Human Endogenous Retrovirus W (OR=19.31; CI 95%: 6.74-55.29; p<0.001), Chlamydophila pneumoniae (OR=6.34; CI 95%: 2.83-14.19; p<0.001), Chlamydophila psittaci (OR=29.05; CI 95%: 8.91-94.70; p<0.001) and Toxoplasma gondii (OR=2.70; CI 95%: 1.34-4.42; p=0.005). The implications of these findings are discussed and further research options are also explicated. [PubMed Citation] [Order full text from Infotrieve]

5) Lipkin WI, Briese T, Hornig M
Borna disease virus - fact and fantasy.
Virus Res. 2011 Dec;162(1-2):162-72.
The occasion of Brian Mahy's retirement as editor of Virus Research provides an opportunity to reflect on the work that led one of the authors (Lipkin) to meet him shortly after the molecular discovery and characterization of Borna disease virus in the late 1980s, and work with authors Briese and Hornig to investigate mechanisms of pathogenesis and its potential role in human disease. This article reviews the history, molecular biology, epidemiology, and pathobiology of bornaviruses. [PubMed Citation] [Order full text from Infotrieve]

6) Aslan M, Kocazeybek B, Turan N, Karakose AR, Altan E, Yuksel P, Saribas S, Cakan H, Caliskan R, Torun MM, Balcioglu I, Alpay N, Yilmaz H
Investigation of schizophrenic patients from Istanbul, Turkey for the presence of West Nile virus.
Eur Arch Psychiatry Clin Neurosci. 2012 Mar;262(2):173-7.
Association of some neurotropic viruses like Borna Disease virus and Herpes virus with schizophrenia is better explained. However, the role of West Nile virus (WNV) infection in schizophrenia is not well documented. Therefore, this study was performed to investigate possible association between schizophrenia and presence of antibodies and WNV RNA in schizophrenic patients. For this, 200 blood samples from patients with schizophrenia and 200 from control groups were collected in Istanbul, Turkey. WNV RNA was not detected in any of the 200 patients and 200 controls analyzed by real-time RT-PCR. One hundred and twelve sera of schizophrenic patients and 162 of controls were analyzed for the presence of IgG antibodies to WNV by a commercial IgG-ELISA (Euroimmun, Germany). Antibodies to WNV were detected in 6 schizophrenic patients and 5 controls. ELISA positive patients had antipsychotic therapy. The difference between groups in terms of seropositivity to WNV was not statistically significant (p = 0.887, p = 0.148). Known symptoms of schizophrenia were observed in these patients, and interestingly majority had close contact to cats in the past and come from agricultural area of Turkey where potential area of mosquitoes and bird habitat. In conclusion, the results of this study show that antibodies to WNV in people do not seem to be associated with schizophrenia. However, detecting antibodies to WNV in schizophrenic patients suggests that WNV infection should be considered in endemic areas as it may play role in psychiatric diseases. [PubMed Citation] [Order full text from Infotrieve]

7) Song JW, Na KS, Tae SH, Kim YK
Borna disease virus antibody and RNA from peripheral blood mononuclear cells of race horses and jockeys in Korea.
Psychiatry Investig. 2011 Mar;8(1):58-60.
[PubMed Citation] [Order full text from Infotrieve]

8) Sakudo A, Tanaka Y, Ikuta K
Capture of infectious borna disease virus using anionic polymer-coated magnetic beads.
Neurosci Lett. 2011 May 2;494(3):237-9.
Borna disease virus (BDV) is a noncytolytic, neurotrophic virus that infects a range of vertebrates, including all warm-blooded animals and possibly humans. Although BDV infections are thought to cause neurological disorders, evidence of the presence of the virus in tissues or blood of psychiatric patients is limited, possibly due to the low sensitivity of detection methods. Here, a simple method for capturing BDV has been developed using magnetic beads coated with an anionic polymer, poly(methyl vinyl ether-maleic anhydrate). The beads were incubated with lysate from BDV-infected cells, then separated from the supernatant by applying a magnet field and washed. The adsorption of BDV by the beads was confirmed by reverse transcription-polymerase chain reaction and Western blotting, which indicated the presence of the phosphoprotein (P), nucleoprotein (N), and viral genome of BDV on the incubated beads. This method of capture may contribute to the improved detection of BDV. [PubMed Citation] [Order full text from Infotrieve]

9) Rackova S, Janu L, Kabickova H
Borna disease virus (BDV) circulating immunocomplex positivity in addicted patients in the Czech Republic: a prospective cohort analysis.
BMC Psychiatry. 2010;10:70.
[PubMed Citation] [Order full text from Infotrieve]

10) Remlinger-Molenda A, Rybakowski J
[Neuroimmunology of bipolar affective disorder].
Psychiatr Pol. 2010 Jan-Feb;44(1):27-38.
Previous neuroimmunological studies focused mostly on depression, regardless of its diagnostic category. In this paper, the studies on the immunological system in patients with bipolar affective illness, including manic episode, have been presented. Research possibilities of neuroimmunology of affective disorders using molecular-genetic methods have also been shown. The studies on the neuroimmunology of depression have always been connected with studies on changes in the immunological system related to stress situations. Disturbances of the immunological system regulation have features of either decrease or pathological increase of the immunological system, with increased activity of pro-inflammatory cytokines (interleukin 1 and 6, interferon). Some pathogenic role for the disturbances of immunological system in depression is also played by viral infections (herpes, Borna viruses). The changes of the immunological system in mania are mostly similar to those observed during depression. An increase of activity of pro-inflammatory cytokines, connected with the lymphocyte Th1 system is especially evident. Like in depression, the role of viral infections has been pointed out (herpes, Borna, parvovirus B19). The oldest mood-stabilizing drug, lithium, has been shown to have strong action against herpes viruses. Molecular-genetic studies point to an association of some genes of the immunological system with both bipolar disorder and schizophrenia. An association of some genes with a predisposition to depression and efficacy of antidepressant drugs has also been shown. [PubMed Citation] [Order full text from Infotrieve]

11) Heinrich A, Adamaszek M
Anti-Borna disease virus antibody responses in psychiatric patients: long-term follow up.
Psychiatry Clin Neurosci. 2010 Jun;64(3):255-61.
[PubMed Citation] [Order full text from Infotrieve]

12) Na KS, Tae SH, Song JW, Kim YK
Failure to detect borna disease virus antibody and RNA from peripheral blood mononuclear cells of psychiatric patients.
Psychiatry Investig. 2009 Dec;6(4):306-12.
[PubMed Citation] [Order full text from Infotrieve]

13) Rackova S, Janu L, Kabickova H
Borna disease virus circulating immunocomplex positivity and psychopathology in psychiatric patients in the Czech Republic.
Neuro Endocrinol Lett. 2009;30(3):414-20.
[PubMed Citation] [Order full text from Infotrieve]

14) van den Pol AN
Viral infection leading to brain dysfunction: more prevalent than appreciated?
Neuron. 2009 Oct 15;64(1):17-20.
Virus infections of the brain can lead to transient or permanent neurologic or psychiatric dysfunction. Some of the complexities in establishing the causal role of viruses in brain disease are explored here. [PubMed Citation] [Order full text from Infotrieve]

15) Garry CE, Garry RF
Proteomics computational analyses suggest that the bornavirus glycoprotein is a class III viral fusion protein (gamma penetrene).
Virol J. 2009;6:145.
[PubMed Citation] [Order full text from Infotrieve]

16) Thakur R, Sarma S, Sharma B
Role of Borna disease virus in neuropsychiatric illnesses: are we inching closer?
Indian J Med Microbiol. 2009 Jul-Sep;27(3):191-201.
The biological cause of psychiatric illnesses continues to be under intense scrutiny. Among the various neurotropic viruses, Borna disease virus (BDV) is another virus that preferentially targets the neurons of the limbic system and has been shown to be associated with behavioural abnormalities. Presence of various BDV markers, including viral RNA, in patients with affective and mood disorders have triggered ongoing debate worldwide regarding its aetiopathogenic relationship. This article analyses its current state of knowledge and recent advances in diagnosis in order to prove or refute the association of BDV in causation of human neuropsychiatric disorders. This emerging viral causative association of behavioural disorders, which seems to be inching closer, has implication not only for a paradigm shift in the treatment and management of neuropsychiatric illnesses but also has an important impact on the public health systems. [PubMed Citation] [Order full text from Infotrieve]

17) Ovanesov MV, Ayhan Y, Wolbert C, Moldovan K, Sauder C, Pletnikov MV
Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection.
J Neuroinflammation. 2008;5:50.
Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to certain neuronal populations. Since persistent BDV infection of neurons is nonlytic in vitro, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brains remain unclear. Our previous studies have shown that activation of microglia by BDV in culture requires the presence of astrocytes as neither the virus nor BDV-infected neurons alone activate microglia. Here, we evaluated the mechanisms whereby astrocytes can contribute to activation of microglia in neuron-glia-microglia mixed cultures. We found that persistent infection of neuronal cells leads to activation of uninfected astrocytes as measured by elevated expression of RANTES. Activation of astrocytes then produces activation of microglia as evidenced by increased formation of round-shaped, MHCI-, MHCII- and IL-6-positive microglia cells. Our analysis of possible molecular mechanisms of activation of astrocytes and/or microglia in culture indicates that the mediators of activation may be soluble heat-resistant, low molecular weight factors. The findings indicate that astrocytes may mediate activation of microglia by BDV-infected neurons. The data are consistent with the hypothesis that microglia activation in the absence of neuronal damage may represent initial steps in the gradual neurodegeneration observed in brains of neonatally BDV-infected rats. [PubMed Citation] [Order full text from Infotrieve]

18) Matsunaga H, Tanaka S, Fukumori A, Tomonaga K, Ikuta K, Amino N, Takeda M
Isotype analysis of human anti-Borna disease virus antibodies in Japanese psychiatric and general population.
J Clin Virol. 2008 Nov;43(3):317-22.
[PubMed Citation] [Order full text from Infotrieve]

19) Flower RL, Kamhieh S, McLean L, Bode L, Ludwig H, Ward CM
Human Borna disease virus infection in Australia: serological markers of infection in multi-transfused patients.
APMIS Suppl. 2008;(124):89-93.
Borna disease virus (BDV) causes neurological disease in horses, however, there is no consensus as to the extent or significance of human infection. BDV antigen levels in plasma (BDVpAg) and anti-BDV were measured by ELISAs. Confirmation was by Western blot (WB), immunofluorescence assay (IFA) or BDV-peptide-epitope ELISA. For 42 volunteers psychiatrically-defined as non-depressed (82 samples) neither BDVpAg nor anti-BDV was detected. For 104 patients with diagnosed depression (290 samples) 1 was BDVpAg positive and 5 anti-BDV positive, one epitope-e8 positive and 4 IFA positive, with 96% concordance for repeat samples. No BDVpAg was detected in 214 pregnant women, 2 were anti-BDV positive, one WB-confirmed (p24/p40). For 219 donors 2 were BDVpAg positive with anti-BDV detected in 5 (2.3%) one IFA 1:10, another IFA 1:40/epitope-e8 positive. In multitransfused patients, 3/168 were BDV pAg positive, with 14/168 anti-BDV positive, 1 epitope-e8 positive, 2 WB positive and 1 IFA 1:10. In BDVpAg positive multi-transfused patients there was an elevated risk of transaminitis. In one case, a patient BDV-negative prior to transfusion was BDVpAg positive for several months posttransfusion (associated with transaminitis). These data provide serological evidence, supported by confirmatory assays and repeat-sample concordance, of BDV infection in Australia, particularly in multi-transfused patients. [PubMed Citation] [Order full text from Infotrieve]

20) Donfrancesco R, Gregori P, Vulcano A, Candelori E, Ronchetti R, Miano S, Pagani J, Villa MP, Patti AM
Borna disease virus infection in children with psychiatric disorders.
APMIS Suppl. 2008;(124):80-2.
[PubMed Citation] [Order full text from Infotrieve]