Ludwig H, Bode L.
Borna disease virus: new aspects
on infection, disease, diagnosis and epidemiology.
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]
L, Ludwig H.
Borna disease virus infection, a human mental-health
Clin Microbiol Rev. 2003 Jul;16(3):534-45.
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.
viro-psycho-immunological disease-model of a subtype affective disorder.
"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.
serum antibodies recognizing linear epitopes of Borna disease virus proteins.
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
Low avidity of human serum antibodies for Borna disease virus
antigens questions their diagnostic value
"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."
Borna disease virus and human disease.
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]
O, Baleyte JM, Mazet P, Fillet AM.
Borna disease virus and psychiatry.
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."
K, Ibrahim MS, Kobayashi T, Tomonaga K.
Borna disease virus and infection
Front Biosci. 2002 Feb 1;7:d470-95.
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."
Sauder C, de la Torre JC.
and reproducibility of RT-PCR to detect Borna disease virus (BDV) RNA in blood:
implications for BDV epidemiology.
J Virol Methods. 1998
"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]
L, Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE, Ludwig H.
disease virus-specific circulating immune complexes, antigenemia, and free antibodies--the
key marker triplet determining infection and prevailing in severe mood disorders.
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."
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
"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."
Rott R, Herzog S, Richt J, Stitz L.
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
la Torre JC.
Bornavirus and the brain.
Dis. 2002 Dec 1;186 Suppl 2:S241-7. [Abstract]
S, Yoshimura M, Motoi Y, Arima K, Aizawa T, Ikuta K, Tashiro M, Ikeda K.
of Borna disease virus genome in normal human brain tissue.
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
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.
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]
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
of Borna Disease Virus from Human Brain Tissue
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
[Isolation of Borna
disease virus from the autopsy brain of a schizophrenia patient]
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."
Kamitani W, Ono E, Yoshino S, Kobayashi T, Taharaguchi
S, Lee BJ, Yamashita M, Kobayashi T, Okamoto M, Taniyama H, Tomonaga K, Ikuta
Glial expression of Borna disease virus phosphoprotein induces
behavioral and neurological abnormalities in transgenic mice.
Natl Acad Sci U S A. 2003 Jul 22;100(15):8969-74. Epub 2003 Jul 11.
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]
M, Solbrig M, Horscroft N, Weissenbock H, Lipkin WI.
virus infection of adult and neonatal rats: models for neuropsychiatric disease.
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)."
TW, Enbergs HK, Muller H.
Experimental and natural borna disease
virus infections: presence of viral RNA in cells of the peripheral blood.
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]
MV, Koob GF, Fallon JH, Reid S, Lipkin WI.
Prefrontal cortex dysfunction
in Borna disease virus (BDV)--infected rats.
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."
Solbrig MV, Koob GF, Joyce JN, Lipkin WI.
neural substrate of hyperactivity in borna disease: changes in brain dopamine
Virology. 1996 Aug 15;222(2):332-8.
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]
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.
disease virus in human brains with a rare form of hippocampal degeneration but
not in brains of patients with common neuropsychiatric disorders.
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]
MV, Koob GF, Lipkin WI.
Key role for enkephalinergic tone in cortico-striatal-thalamic
Eur J Neurosci. 2002 Nov;16(9):1819-22.
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."
MV, Rubin SA, Schwartz GJ, Moran TH, Sobotka TJ, Carbone KM.
neonatal Borna disease virus (BDV) infection of the brain causes chronic emotional
abnormalities in adult rats.
Physiol Behav. 1999 Jul;66(5):823-31.
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."
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.
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]
Peter, Sauder, Christian, Hausmann, Jurgen, Ehrensperger, Felix, Schwemmle, Martin
of Borna disease virus
J Gen Virol 2000 81: 2123-2135 [Full
Nakaya T, Kuratsune H, Kitani T, Ikuta K.
on Borna disease virus in patients with chronic fatigue syndrome]
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.
of evidence of Borna disease virus infection in Swedish patients with Chronic
J Neurovirol. 1999 Oct;5(5):495-9.
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]
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.
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."
T, Takahashi H, Nakamur Y, Kuratsune H, Kitani T, Machii T, Yamanishi K, Ikuta
Borna disease virus infection in two family clusters of patients
with chronic fatigue syndrome.
Microbiol Immunol. 1999;43(7):679-89.
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]
IH, Christensen LS, Jensen B, Danneskiold-Samsee B, Bliddal H, Wiik A.
for Borna disease virus in Danish fibromyalgia patients.
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
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
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
Detection of Borna Disease Virus-Reactive Antibodies from Patients
with Psychiatric Disorders and from Horses by Electrochemiluminescence Immunoassay
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
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.
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.
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]
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.
"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]
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.
"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]
TJ, Dietrich DE, Emrich HM.
Possible use of amantadine in depression.
"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]
R, Severus E, Bode L, Brehm M, Kuhl K-P, Berzewski H, Ludwig H.
Borna disease virus in affective disorders.
"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
Bode L, Ferszt R, Czech G.
virus infection and affective disorders in man.
"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]
R, Herzog S, Bechter K, Frese K.
Borna disease, a possible hazard
Arch Virol. 1991;118(3-4):143-9.
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]
R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W, Koprowski H.
of serum antibodies to Borna disease virus in patients with psychiatric disorders.
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."
JD, Winokur A, Dyson W, Herzog S, Gonzalez F, Rott R, Koprowski H.
disease virus. A possible etiologic factor in human affective disorders?
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]
ZF, Amsterdam JD, Kao M, Shankar V, Koprowski H, Dietzschold B.
of Borna disease virus-reactive antibodies from patients with affective disorders
by western immunoblot technique.
J Affect Disord. 1993 Jan;27(1):61-8.
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]
CH, Chiu YL, Wei FC, Koong FJ, Liu HC, Shaw CK, Hwu HG, Hsiao KJ.
seroprevalence of Borna virus infection in schizophrenic patients, family members
and mental health workers in Taiwan.
Mol Psychiatry. 1999
"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]
Yasuhide, Takahashi, Kazuo, Peng, Xie, Fukuda, Koji, Ohno, Koei, Ogawa, Tsuguhiro,
Gonda, Kenji, Mori, Norio, Niwa, Shin-ichi, Shigeta, Shiro
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
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
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]
Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2003 Mar;17(1):85-7.
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."
C, Muller, A, Cubitt, B, Mayer, J, Steinmetz, J, Trabert, W, Ziegler, B, Wanke,
K, Mueller-Lantzsch, N, de la Torre, JC, Grasser, FA
Borna disease virus (BDV) antibodies and BDV RNA in psychiatric patients: evidence
for high sequence conservation of human blood-derived BDV RNA
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."
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.
"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.
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]
K, Watanabe M, Nakamura K, Suwaki H, Nakaya T, Nakamura Y, Takahashi H, Ikuta
Clinical investigation of the relationship between Borna disease
virus (BDV) infection and schizophrenia in 67 patients in Japan.
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]
RW 2nd, Buchanan RW, Summerfelt A, Breier A, Carpenter WT Jr, Bryant NL, Rubin
SA, Carbone KM.
Borna disease virus and schizophrenia.
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]
AM, Carbone KM, Yolken RH.
Polymerase chain reaction (PCR) search
for viral nucleic acid sequences in schizophrenia.
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."
Planz O, Rziha HJ, Stitz L.
relationship of Borna disease virus isolates.
"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."
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
Mol Psychiatry. 1999 Nov;4(6):566-71.
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]
F, Sawada T, Yamaguchi K, Rajewski A, Rybakowski J.
Virus--reactive antibodies in Polish psychiatric patients.
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
"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]
JP, van Vliet K, Pleyte W, Herzog S, Hoek HW, van Loon AM.
disease virus and schizophrenia in Surinamese immigrants to the Netherlands.
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."
K, Toyomasu K, Imamura Y, Maeda H, Toyoda T.
No association of borna
disease virus with psychiatric disorders among patients in northern Kyushu, Japan.
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]
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.
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]
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
Clin. Diagn. Lab. Immunol. 1997 4: 189-194
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
Nowotny, Norbert, Kolodziejek, Jolanta,
Jehle, Christian O., Suchy, Angelika, Staeheli, Peter, Schwemmle, Martin
and Characterization of a New Subtype of Borna Disease Virus
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." [Full