Medline search on Borna Virus and Psychiatric Disorders

MEDLINE Search By, Ivan Goldberg, M.D.

1. BMC Psychiatry. 2010 Sep 8;10:70.

Borna disease virus (BDV) circulating immunocomplex positivity in addicted
patients in the Czech Republic: a prospective cohort analysis.

Rackova S, Janu L, Kabickova H.

Psychiatric Department, University Hospital, Medical Faculty Charles University
in Pilsen, Alej svobody 80, Pilsen 301 00, Czech Republic. rackova@fnplzen.cz

BACKGROUND: Borna disease virus (BDV) is an RNA virus belonging to the family
Bornaviridae. Borna disease virus is a neurotropic virus that causes changes in
mood, behaviour and cognition. BDV causes persistent infection of the central
nervous system. Immune changes lead to activation of infection. Alcohol and drug 
dependence are associated with immune impairment. METHODS: We examined the
seropositivity of BDV circulating immunocomplexes (CIC) in patients with alcohol 
and drug dependence and healthy individuals (blood donors). We examined 41
addicted patients for the presence of BDV CIC in the serum by ELISA at the
beginning of detoxification, and after eight weeks of abstinence. This is the
first such study performed in patients with alcohol and drug dependence. RESULTS:
BDV CIC positivity was detected in 36.59% of addicted patients on day 0 and in
42.86% on day 56. The control group was 37.3% positive. However, we did not
detect higher BDV CIC positivity in addicted patients in comparison with blood
donors (p = 0.179). The significantly higher level of BDV CIC was associated with
lower levels of GGT (gamma glutamyl transferase) (p = 0.027) and approached
statistical significance with the lower age of addicted patients (p = 0.064). We 
did not find any association between BDV CIC positivity and other anamnestic and 
demographic characteristics. CONCLUSIONS: In our study addicted patients did not 
have significantly higher levels of BDV CIC than the control group. The highest
levels of BDV CIC were detected in patients with lower levels of GGT and a lower 
age. TRIAL REGISTRATION: This study was approved by the ethical committee of the 
University Hospital Medical Faculty of Charles University in Pilsen, Czech
Republic (registration number 303/2001).


PMCID: PMC2944235
PMID: 20825673 [PubMed - indexed for MEDLINE]


2. Psychiatr Pol. 2010 Jan-Feb;44(1):27-38.

[Neuroimmunology of bipolar affective disorder]

[Article in Polish]

Remlinger-Molenda A, Rybakowski J.

Klinika Psychiatrii Doros?ych UM w Poznaniu.

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.


PMID: 20449978 [PubMed - indexed for MEDLINE]


3. Psychiatry Investig. 2009 Dec;6(4):306-12. Epub 2009 Nov 5.

Failure to detect borna disease virus antibody and RNA from peripheral blood
mononuclear cells of psychiatric patients.

Na KS, Tae SH, Song JW, Kim YK.

Department of Psychiatry, College of Medicine, Korea University, Seoul, Korea.

OBJECTIVE: Borna disease virus (BDV) is a highly neurotropic agent causing
various neuropsychiatric symptoms in animals. Over the past two decades, it has
been suggested that BDV might be associated with human psychiatric diseases. We
aimed to investigate whether BDV is associated with psychiatric patients in
Korea. METHODS: We recruited 60 normal controls and 198 psychiatric patients (98 
patients with depressive disorder, 60 with schizophrenia, and 40 with bipolar
disorder). We used an indirect immunofluorescence antibody (IFA) test for the BDV
antibody and a real-time reverse transcriptase polymerase chain reaction
(rRT-PCR) assay for p24 and p40 RNA from peripheral blood mononuclear cells
(PBMCs). RESULTS: Neither the BDV antibody nor p24, p40 RNA was detected in
controls and patients groups. CONCLUSION: Our results suggest that BDV might not 
be associated with psychiatric patients in Korea.


PMCID: PMC2808801
PMID: 20140130 [PubMed]


4. Indian J Med Microbiol. 2009 Jul-Sep;27(3):191-201.

Role of Borna disease virus in neuropsychiatric illnesses: are we inching closer?

Thakur R, Sarma S, Sharma B.

Department of Microbiology, IHBAS, Dilshad Garden, Delhi, India.
drrajeevthakur@rediffmail.com

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.


PMID: 19584498 [PubMed - indexed for MEDLINE]


5. Neuro Endocrinol Lett. 2009;30(3):414-20.

Borna disease virus circulating immunocomplex positivity and psychopathology in
psychiatric patients in the Czech Republic.

Rackova S, Janu L, Kabickova H.

Department of Psychiatry, University Hospital, Medical Faculty, Charles
University in Pilsen, Alej svobody 80, Pilsen, Czech Republic. rackova@fnplzen.cz

OBJECTIVES: Borna disease virus (BDV) is an RNA virus belonging to the family
Bornaviridae. BDV is a neurotropic virus that causes changes in mood, behaviour
and cognition. Patients with psychiatric disorders have a higher incidence of BDV
positivity than healthy individuals. METHODS: We examined the seropositivity of
BDV circulating immunocomplexes (CIC) in psychiatric patients and healthy
individuals (blood donors). We examined 39 psychiatric inpatients for the
presence of BDV CIC in the serum by ELISA on day 0, 28 and 56. During the same
period psychopathology was measured using psychiatric scales (CGI, CGI-I, MADRS, 
SDS, PANSS). This is the first such study performed in the Czech Republic.
RESULTS: BDV CIC positivity was detected in 66.7% of psychiatric patients (26/39)
on day 0, in 53.9% (14/26) on day 28 and in 52.9% on day 56 (9/17). The control
group was 22.2% (28/126) positive. The incidence of BDV CIC was significantly
higher in psychiatric patients than in healthy individuals (p=0.001). The
significantly higher level of BDV CIC was associated with the higher severity of 
psychopathology in comparison with patients with mild or moderate psychopathology
(p=0.03). We did not find any association between BDV CIC positivity and other
characteristics (age, diagnosis, family, personal history, the history of
infectious diseases, contact with animals). CONCLUSION: In our study psychiatric 
patients had significantly higher levels of BDV CIC than the control group. The
highest levels of BDV CIC were detected in patients with more severe
psychopathology.


PMID: 19855370 [PubMed - indexed for MEDLINE]


6. Pharmacopsychiatry. 2008 Sep;41(5):202-3. Epub 2008 Sep 1.

Amantadine reduces mania in borna disease virus-infected non-psychotic bipolar
patients.

Ohlmeier MD, Zhang Y, Bode L, Sieg S, Feutl S, Ludwig H, Emrich HM, Dietrich DE.

PMID: 18763224 [PubMed - indexed for MEDLINE]


7. APMIS Suppl. 2008;(124):66-9.

The history and treatment of a bipolar patient diagnosed with Borna disease virus
infection. Case report.

[No authors listed]

A description of Bipolar Disorder and its treatment costs. The prevalence of
various psychiatric disorders in the United States in which Borna Disease Virus
(BDV) may play a role. My personal history of Bipolar Disorder including:
diagnoses and treatment of Borna Disease Virus infection.


PMID: 18771102 [PubMed - indexed for MEDLINE]


8. APMIS Suppl. 2008;(124):61-5.

Human Borna disease virus-infection and its therapy in affective disorders.

Dietrich DE, Bode L.

Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Medical School
Hannover, Germany. dietrich.detlef@mh-hannover.de

Patients with affective disorders show an enhanced prevalence of Borna disease
virus (BDV)-infection. Furthermore, BDV causes latent infection preferably in
limbic central nervous structures and is suggested to be causally related to
subtypes of affective disorders, especially with melancholic clinical features or
bipolarity. Such a possible link was highlighted by the first report of
amantadine showing an antidepressive and an antiviral efficacy against BDV in a
patient with a bipolar disorder. This article summarizes clinical studies which
followed this first report on the use of amantadine in BDV-infected patients with
an affective disorder. A special focus is given on an open clinical study in
patients with depression (n = 25), a study in remitted patients with affective
disorders (n = 16), and the effect of amantadine on severe hypomanic or
moderately manic patients with a bipolar disorder in an on-off-on study. In these
studies amantadine reduced clinical symptoms paralleled by a reduction of
BDV-infection in depressive patients, it also reduced all three BDV-parameters
(BDV-Ab, -AG, and -CICs) in remitted patients, and it even reduced severe
hypomania and moderate mania in bipolar patients. These data suggest the
existence of an etiopathogenetic link between BDV and subtypes of affective
disorders.


PMID: 18771101 [PubMed - indexed for MEDLINE]


9. J Clin Lab Anal. 2008;22(4):314-20.

RNA from Borna disease virus in patients with schizophrenia, schizoaffective
patients, and in their biological relatives.

Nunes SO, Itano EN, Amarante MK, Reiche EM, Miranda HC, de Oliveira CE, Matsuo T,
Vargas HO, Watanabe MA.

Department of Psychiatry, State University of Londrina, Londrina, PR, Brazil.

Numerous interactions of the immune system with the central nervous system have
been described recently. Mood and psychotic disorders, such as severe depression 
and schizophrenia, are both heterogeneous disorders regarding clinical
symptomatology, the acuity of symptoms, the clinical course, the treatment
response, and probably also the etiology. Detection of p24 RNA from Borna disease
virus (BDV) by the reverse transcriptase polymerase chain reaction in patients
with schizophrenia, schizoaffective disorder, and in their biological relatives
was evaluated. The subjects were 27 schizophrenic and schizoaffective patients,
27 healthy controls, 20 relatives without psychiatric disease, and 24 relatives
with mood disorder, who attended the Psychiatric Ambulatory of Londrina State
University, Paraná, Brazil. The subjects were interviewed by structured
diagnostic criteria categorized according to the Diagnostic and Statistical
Manual of Mental Disorders-IV, axis I, (SCID-IV). The mean duration of illness in
schizophrenic and schizoaffective patients was 15.341+/-1.494 years and the
median age at onset was 22.4+/-7.371 years. There were no significant differences
in gender (P=0.297), age (P=0.99), albumin (P=0.26), and body mass index
(kg/m(2)) (p=0.28), among patients, controls, and relatives. Patients and
biological relatives had significantly higher positive p24 RNA BDV detection than
controls (P=0.04); however, the clinical significance of BDV remains to be
clarified.


PMID: 18623121 [PubMed - indexed for MEDLINE]


10. J Clin Virol. 2006 Aug;36(4):309-11. Epub 2006 Jul 5.

Failure to detect Borna disease virus antigen and RNA in human blood.

Wolff T, Heins G, Pauli G, Burger R, Kurth R.

Comment in:
    J Clin Virol. 2006 Aug;36(4):312-3; author reply 314.

BACKGROUND: Borna disease virus (BDV) is the etiological agent of a rare
progressive meningoencephalitis that affects mostly horses and sheep. There is an
unresolved debate whether also humans are susceptible to infection with BDV and
if so, whether this might be associated with neuropsychiatric diseases. One
recent key publication employing an ELISA-based sandwich assay reported
prevalences of BDV-specific circulating immune complexes in human blood as high
as 30% in the normal population and up to 100% in psychiatric patients [Bode L,
Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE, et al. 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;6(4):481-91]. However, this report did not
examine for the physical presence of BDV antigens in human blood, and therefore, 
these seemingly high prevalences may not reflect Borna virus-specific signals.
OBJECTIVES: We attempted to correlate string plasma signals in the particular
sandwich ELISA system with the presence of BDV antigens. STUDY DESIGN: Four
preselected plasma samples with high reactivity in the described assay were
analysed by immunoaffinity purification and highly sensitive real-time RT-PCR.
RESULTS: Neither method did provide any evidence for the presence of viral
proteins or nucleic acids. CONCLUSIONS: Our findings argue against the concept
that the described sandwich ELISA reliably detects BDV-specific antigens in human
blood, therefore do not support the hypothesis that BDV is a pathogen of humans.


PMID: 16822717 [PubMed - indexed for MEDLINE]


11. Zhonghua Liu Xing Bing Xue Za Zhi. 2006 Jun;27(6):479-82.

[Study on molecular epidemiology of Borna disease virus in Ningxia and vicinal
regions]

[Article in Chinese]

Wang ZH, Xie P, Han YX, Zhan J.

Department of Multiple Disease, The Affiliated Hospital of Ningxia Medical
College, Yinchuan 750004, China.

OBJECTIVE: In order to investigate the epidemics of borna disease virus (BDV) in 
Ningxia and its vicinal regions. METHODS: p24 fragment of BDV from: (1)
peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid mononuclear
cells (CSFMC) from 52 patients with viral encephalitis (VE) and 32 healthy
donors, (2) peripheral blood mononuclear cells (PBMC) from 53 patients with
depressive disorder (DD) and from 360 sheep, were examined by nested reverse
transcriptase polymerase chain reaction(PCR) with fluorescence quantitative PCR. 
Gene sequence and amino acid sequence were analysed for positive product and the 
molecular epidemiologic characteristics by drawing phylogenetic trees. RESULTS:
The positive rate of BDV p24 in CSFMC from VE (11.54%) and in PBMC from DD 11.32%
was significantly higher than that in healthy donors (0%) (P < 0.05). The
phylogenetic trees indicating the genetic relationship of the p24 fragment of BDV
in both sheep and VE, DD in China and was similar to the nucleotide sequence of
H1766 strain in Germany. CONCLUSION: Data indicated that the BDV infection was
possibly existing in VE, DD patients and health sheep in Ningxia and its vicinal 
regions with confined locality which called for further study.


PMID: 17152506 [PubMed - indexed for MEDLINE]


12. J Affect Disord. 2006 Jan;90(1):43-7. Epub 2005 Dec 1.

Detection of Borna disease virus p24 RNA in peripheral blood cells from Brazilian
mood and psychotic disorder patients.

Miranda HC, Nunes SO, Calvo ES, Suzart S, Itano EN, Watanabe MA.

Department of Pathological Sciences-Immunology, Londrina State University,
Londrina, PR, Brazil.

BACKGROUND: Borna disease virus (BDV) is a virus that naturally infects a broad
range of warm-blooded animals. BDV is an enveloped virus, non-segmented,
negative-stranded RNA genome and has an organization characteristic of a member
of Bornaviridae in the order of Mononegavirale. In the present work we
investigated the presence of BDV p24 RNA in peripheral blood cells from 30
psychiatric patients (19 with mood disorder and 11 with psychotic disorder) and
30 healthy volunteers as the control group. METHODS: All subjects were
interviewed by structured diagnostic criteria categorized according to the
DSM-IV, Axis I (SCID-V). The presence of BDV p24 RNA was investigated by nested
reverse transcriptase PCR (RT-PCR) using specific primers to p24 from BDV. The
specificity of the detection was analyzed by the sequencing of PCR products.
RESULTS: The mean duration of illness in mood and psychotic patients with p24 RNA
of BDV was 25 (+/-12.3) years and the median age was 43.77 (+/-15.2) years. There
were no significant differences in gender and age among patients and control
group, neither duration of illness among patients with mood and psychotic
disorders in the presence or absence of p24 RNA of BDV. We found a frequency of
33.33% (10/30) of BDV-RNA on patient's group and 13.33% (4/30) on control group. 
The given sequences revealed identity with GenBank database sequence for BDV.
CONCLUSION: The detection of a higher level of BDV-RNA in the peripheral blood
cells of patients than on control group should help our understanding of the
pathogenesis in the disease.


PMID: 16324750 [PubMed - indexed for MEDLINE]


13. Clin Diagn Lab Immunol. 2005 May;12(5):671-6.

Detection by radioligand assay of antibodies against Borna disease virus in
patients with various psychiatric disorders.

Matsunaga H, Tanaka S, Sasao F, Nishino Y, Takeda M, Tomonaga K, Ikuta K, Amino
N.

Department of Psychiatry, Osaka General Medical Center, Bandai-higashi 3-1-56,
Sumiyoshi-ku, Osaka 558-8558, Japan. matsuh@osk.3web.ne.jp

Using a radioligand assay, which preserves the natural form of the antigen,
antibodies against Borna disease virus nucleoprotein and phosphoprotein were
detected in 11 and 19 sera of 171 psychiatric patients, respectively. Compared
with results by Western blotting, three and nine sera were concordantly positive,
respectively. The four sera showing the highest levels of antibodies by
radioligand assay were all negative by Western blotting; however, dilution and
inhibition tests supported the positive results. Our results suggest the
importance of conformational structure to detect human anti-Borna disease virus
antibodies.


PMCID: PMC1112074
PMID: 15879032 [PubMed - indexed for MEDLINE]


14. Psychiatry Res. 2005 Mar 30;134(1):105; author reply 106.

Detection of anti-Borna disease virus antibodies by Western blot analysis.

Ghosh M, Sauder C, Carbone KM, Malik TH.

Comment on:
    Psychiatry Res. 2003 Sep 30;120(2):201-6.

PMID: 15808296 [PubMed - indexed for MEDLINE]


15. FASEB J. 2004 May;18(7):863-5. Epub 2004 Mar 19.

Persistent, noncytolytic infection of neurons by Borna disease virus interferes
with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis.

Hans A, Bajramovic JJ, Syan S, Perret E, Dunia I, Brahic M, Gonzalez-Dunia D.

Unité des Virus Lents, CNRS URA 1930, Institut Pasteur, Paris, France.

Infection of the central nervous system by Borna disease virus (BDV) provides a
unique model to study the mechanisms whereby a persistent viral infection can
impair neuronal function and cause behavioral diseases reminiscent of mood
disorders, schizophrenia, or autism in humans. In the present work, we studied
the effect of BDV infection on the response of hippocampal neurons, the main
target for this virus, to the neurotrophin BDNF. We showed that persistent
infection did not affect neuronal survival or morphology. However, it blocked
BDNF-induced ERK 1/2 phosphorylation, despite normal expression of the TrkB BDNF 
receptor. In addition, BDNF-induced expression of synaptic vesicle proteins was
abrogated, which resulted in severely impaired synaptogenesis and defects in
synaptic organization. Thus, we provide the first evidence that a virus can
interfere specifically with neurotrophin-regulated neuroplasticity, thereby
hampering proper neuronal connectivity. These results may help to understand the 
behavioral disorders associated with BDV infection.


PMID: 15033926 [PubMed - indexed for MEDLINE]


16. Psychiatry Res. 2003 Sep 30;120(2):201-6.

Detection of anti-Borna Disease Virus (BDV) antibodies from patients with
schizophrenia and mood disorders in Japan.

Terayama H, Nishino Y, Kishi M, Ikuta K, Itoh M, Iwahashi K.

Department of Neurophysiology, Graduate School of Azabu University, 1-71-1
Futinobe, Sagamihara-shi, Kanagawa 229-8501, Japan.

Comment in:
    Psychiatry Res. 2005 Mar 30;134(1):105; author reply 106.

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.


PMID: 14527651 [PubMed - indexed for MEDLINE]


17. Mol Psychiatry. 2003 May;8(5):469-70.

Hypothalamic-pituitary-adrenal (HPA) system activity in depression and infection 
with Borna disease virus and Chlamydia pneumoniae.

Deuschle M, Bode L, Schnitzler P, Meyding-Lamadé U, Plesch A, Ludwig H, Hamann B,
Heuser I.

PMID: 12808426 [PubMed - indexed for MEDLINE]


18. Schizophr Res. 2002 Oct 1;57(2-3):303-5.

Borna disease virus and psychiatric disorders.

Lebain P, Vabret A, Freymuth F, Brazo P, Chabot B, Dollfus S, Henri B.

PMID: 12223262 [PubMed - indexed for MEDLINE]


19. Mol Psychiatry. 2001 Jul;6(4):481-91.

Borna disease virus-specific circulating immune complexes, antigenemia, and free 
antibodies--the key marker triplet determining infection and prevailing in severe
mood disorders.

Bode L, Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE, Ludwig H.

Project Bornavirus Infections, Robert Koch-Institut, Nordufer 20, 13353 Berlin,
Germany. bodel@rki.de

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.


PMID: 11443538 [PubMed - indexed for MEDLINE]


20. Eur Psychiatry. 2001 Feb;16(1):3-10.

Borna disease virus and psychiatry.

Taieb O, Baleyte JM, Mazet P, Fillet AM.

Department of Virology, CERVI, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.

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.


PMID: 11246286 [PubMed - indexed for MEDLINE]


21. J Clin Microbiol. 2001 Feb;39(2):419-29.

Immunological and PCR analyses for Borna disease virus in psychiatric patients
and blood donors in Japan.

Fukuda K, Takahashi K, Iwata Y, Mori N, Gonda K, Ogawa T, Osonoe K, Sato M, Ogata
S, Horimoto T, Sawada T, Tashiro M, Yamaguchi K, Niwa S, Shigeta S.

Department of Microbiology, Fukushima Medical University, Fukushima-shi,
Fukushima 960-1295, Japan.

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.


PMCID: PMC87754
PMID: 11158085 [PubMed - indexed for MEDLINE]


22. J Psychiatr Res. 2000 Nov-Dec;34(6):393-6.

Borna disease virus-related therapy-resistant depression improved after
cerebrospinal fluid filtration.

Bechter K, Herzog S, Schreiner V, Brinkmeier H, Aulkemeyer P, Weber F, Wollinsky 
KH, Schüttler R.

Department of Psychiatry II, University of Ulm, Ludwig-Heilmeyer-Strasse 2, 89312
Bezirkskrankenhaus Günzburg, Germany. dr.bechter@bkh-guenzburg.de

PMID: 11165306 [PubMed - indexed for MEDLINE]


23. Rev Sci Tech. 2000 Apr;19(1):259-88.

Borna disease virus: new aspects on infection, disease, diagnosis and
epidemiology.

Ludwig H, Bode L.

Institute of Virology, Free University Berlin, Königin-Luise-Strasse 49, 14195
Berlin, Germany.

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.


PMID: 11189720 [PubMed - indexed for MEDLINE]


24. Bipolar Disord. 2000 Mar;2(1):65-70.

Amantadine in depressive patients with Borna disease virus (BDV) infection: an
open trial.

Dietrich DE, Bode L, Spannhuth CW, Lau T, Huber TJ, Brodhun B, Ludwig H, Emrich
HM.

Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover,
Germany. dietrich.detlef@mh-hannover.de

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.


PMID: 11254023 [PubMed - indexed for MEDLINE]


25. Psychiatr Pol. 1999 Nov-Dec;33(6):947-58.

[Transmission of Borna disease virus as etiopathogenetic factor in schizophrenia 
and affective disorders]

[Article in Polish]

Rybakowski F.

Kliniki Psychiatrii Dzieci i M?odziezy AM w Poznaniu.

Borna Disease Virus (BDV) is a negative single-stranded ribonucleic acid (RNA)
virus, showing strong neurotropism. BDV may infect many different warm-blooded
animal species, causing neurological and behavioral disorders.
Seroepidemiological studies suggest the existence of human infections with BDV
and their higher prevalence in psychiatric patients. Using different serological 
assays, anti-BDV antibodies were found in about 10%-20% of patients with
schizophrenia, and in 1%-2% of the control group of healthy subjects. There are
also reports on BDV antigens and BDV RNA in peripheral blood mononuclear cells of
human subjects, and in the brain tissue examined during the autopsy in patients
with psychiatric disorders. Higher prevalence of BDV infection markers was also
found in the group of patients with affective illness. A hypothesis was put
forward on the activation of BDV-infection in patients with affective illness
during acute episode. There are also reports on higher BDV-seropositivity in
various psychiatric disorders compared with healthy control subjects. It also
would be purposeful to study a possibility of BDV infections in patients with
psychiatric disturbances, having their onset in childhood or adolescence.


PMID: 10776031 [PubMed - indexed for MEDLINE]


26. Clin Diagn Lab Immunol. 1999 Sep;6(5):696-700.

Detection of borna disease virus-reactive antibodies from patients with
psychiatric disorders and from horses by electrochemiluminescence immunoassay.

Yamaguchi K, Sawada T, Naraki T, Igata-Yi R, Shiraki H, Horii Y, Ishii T, Ikeda
K, Asou N, Okabe H, Mochizuki M, Takahashi K, Yamada S, Kubo K, Yashiki S,
Waltrip RW 2nd, Carbone KM.

Blood Transfusion Service and Internal Medicine, Kumamoto University School of
Medicine, Kumamoto, Japan. kyama@gpo.kumamoto-u.ac.jp

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.


PMCID: PMC95757
PMID: 10473520 [PubMed - indexed for MEDLINE]


27. Pharmacopsychiatry. 1999 Jul;32(4):142-7.

Amantadine revisited: an open trial of amantadinesulfate treatment in chronically
depressed patients with Borna disease virus infection.

Ferszt R, Kühl KP, Bode L, Severus EW, Winzer B, Berghöfer A, Beelitz G, Brodhun 
B, Müller-Oerlinghausen B, Ludwig H.

Department of Gerontopsychiatry, Freie Universität Berlin, Germany.
ferszt@zedat.fu-berlin.de

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.


PMID: 10505484 [PubMed - indexed for MEDLINE]


28. Pharmacopsychiatry. 1999 May;32(3):93-8.

Activated Borna disease virus in affective disorders.

Ferszt R, Severus E, Bode L, Brehm M, Kühl K-P, Berzewski H, Ludwig H.

Department of Gerontopsychiatry, Free University of Berlin, Germany.
ferszt@zedat.fu-berlin.de

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.


PMID: 10463375 [PubMed - indexed for MEDLINE]


29. J Neurovirol. 1999 Apr;5(2):196-9.

Failure to demonstrate Borna disease virus genome in peripheral blood mononuclear
cells from psychiatric patients in Korea.

Kim YK, Kim SH, Choi SH, Ko YH, Kim L, Lee MS, Suh KY, Kwak DI, Song KJ, Lee YJ, 
Yanagihara R, Song JW.

Department of Psychiatry, College of Medicine, Korea University, Seoul.

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.


PMID: 10321984 [PubMed - indexed for MEDLINE]


30. Pharmacopsychiatry. 1999 Mar;32(2):47-55.

Possible use of amantadine in depression.

Huber TJ, Dietrich DE, Emrich HM.

Department of Clinical Psychiatry, Medical School of Hanover, Germany.

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.


PMID: 10333162 [PubMed - indexed for MEDLINE]


31. Pharmacopsychiatry. 1999 Jan;32(1):44-6.

Borna disease in humans--speculations and controversies.

Bechter K.

Comment on:
    Pharmacopsychiatry. 1998 May;31(3):77-82.

PMID: 10071184 [PubMed - indexed for MEDLINE]


32. Lancet. 1998 Dec 5;352(9143):1828-9.

Borna disease virus proteins in cerebrospinal fluid of patients with recurrent
depression and multiple sclerosis.

Deuschle M, Bode L, Heuser I, Schmider J, Ludwig H.

PMID: 9851390 [PubMed - indexed for MEDLINE]


33. J Virol. 1998 Dec;72(12):10044-9.

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.

Iwata Y, Takahashi K, Peng X, Fukuda K, Ohno K, Ogawa T, Gonda K, Mori N, Niwa S,
Shigeta S.

Department of Microbiology, School of Medicine, Fukushima Medical University,
Fukushima-shi, Fukushima, 960-1295, Japan.

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.


PMCID: PMC110530
PMID: 9811743 [PubMed - indexed for MEDLINE]


34. Pharmacopsychiatry. 1998 May;31(3):77-82.

A viro-psycho-immunological disease-model of a subtype affective disorder.

Dietrich DE, Schedlowski M, Bode L, Ludwig H, Emrich HM.

Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover,
Germany.

Comment in:
    Pharmacopsychiatry. 1998 May;31(3):75-6.
    Pharmacopsychiatry. 1999 Jan;32(1):44-6.

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.


PMID: 9657234 [PubMed - indexed for MEDLINE]


35. Brain Res. 1997 Oct 3;770(1-2):307-9.

Detection of Borna disease virus genome in normal human brain tissue.

Haga S, Yoshimura M, Motoi Y, Arima K, Aizawa T, Ikuta K, Tashiro M, Ikeda K.

Department of Ultrastructure and Histochemistry, Tokyo Institute of Psychiatry,
Tokyo, Japan. shaga@prit.go.jp

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.


PMID: 9372235 [PubMed - indexed for MEDLINE]


36. Lancet. 1997 Jun 21;349(9068):1813-4.

Borna disease virus in brains of North American and European people with
schizophrenia and bipolar disorder. Bornavirus Study Group.

Salvatore M, Morzunov S, Schwemmle M, Lipkin WI.

Comment in:
    Lancet. 1997 Aug 23;350(9077):593.
    Lancet. 1997 Aug 23;350(9077):592-3.

PMID: 9269221 [PubMed - indexed for MEDLINE]


37. Lancet. 1997 Mar 29;349(9056):958.

Depression, Borna disease, and amantadine.

Lieb K, Hufert FT, Bechter K, Bauer J, Kornhuber J.

Comment on:
    Lancet. 1997 Jan 18;349(9046):178-9.

PMID: 9093281 [PubMed - indexed for MEDLINE]


38. Clin Diagn Lab Immunol. 1997 Mar;4(2):189-94.

Lack of association of Borna disease virus and human T-cell leukemia virus type 1
infections with psychiatric disorders among Japanese patients.

Kubo K, Fujiyoshi T, Yokoyama MM, Kamei K, Richt JA, Kitze B, Herzog S, Takigawa 
M, Sonoda S.

Department of Neuropsychiatry, Faculty of Medicine, Kagoshima University, Japan.

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.


PMCID: PMC170500
PMID: 9067654 [PubMed - indexed for MEDLINE]


39. Lancet. 1997 Jan 18;349(9046):178-9.

Amantadine and human Borna disease virus in vitro and in vivo in an infected
patient with bipolar depression.

Bode L, Dietrich DE, Stoyloff R, Emrich HM, Ludwig H.

Comment in:
    Lancet. 1997 Mar 29;349(9056):958.

PMID: 9111548 [PubMed - indexed for MEDLINE]


40. Arch Virol Suppl. 1997;13:167-82.

Clinical similarities and close genetic relationship of human and animal Borna
disease virus.

Bode L, Ludwig H.

Department of Virology, Robert Koch-Institut, Berlin, Federal Republic of
Germany.

Borna disease virus (BDV) is the prototype genus of a new family, Bornaviridae,
within the order Mononegavirales. BDV naturally infects animals and man. The
symptomatology in animals ranges from subclinical infection to rare cases of
encephalitis. Asymptomatic infection seemed more frequent than expected, based on
antibody data from 100 healthy horses derived from different stables with a
history of diseased cases (30-40% carriers). Likewise, phasic episodes of a
neurobehavioral syndrome followed by recovery were much more common than fatal
neurologic disease. They were paralleled by expression of BDV antigens (N-protein
p40, P-protein p24) and RNA transcripts in peripheral blood mononuclear cells,
indicating viral activation. Representative longitudinal studies showed that
episodes of depressive illness in humans as well as apathetic phases in infected 
horses were accompanied by antigen expression and followed a similar clinical
course. After recovery, BDV antigen disappeared. This temporal congruence,
together with the recent isolation of infectious BDV from such patients, points
to a contributory role of this virus in human affective disorders. Successful
amelioration of BDV-induced neurobehavioral disease in horses with
antidepressants applied in psychiatry, supported a common viral pathomechanism,
involving reversible disturbances of the neurotransmitter network in the limbic
system. Sequences of genetic material amplified from infected animal tissue and
human PBMCs revealed a close interspecies relationship and high sequence
conservation of the BDV genome. In human BDV isolates, however, single unique
mutations were prominent in four genes. This finding supports the hypothesis that
despite of high genomic conservation, species-specific genotypes may be
definable, provided the sequences are derived from RNA of infectious virus.


PMID: 9413536 [PubMed - indexed for MEDLINE]


41. Intervirology. 1997;40(2-3):185-97.

The neuropathogenesis of Borna disease virus infections.

Ludwig H, Bode L.

Institute of Virology, Free University of Berlin, Germany.

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


PMID: 9450235 [PubMed - indexed for MEDLINE]


42. Mol Psychiatry. 1996 Jul;1(3):200-12.

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

Bode L, Dürrwald R, Rantam FA, Ferszt R, Ludwig H.

Robert Koch-Institut, Federal Institute for Infectious and Non-Communicable
Diseases, Department of Virology, Berlin, Germany.

Comment in:
    Mol Psychiatry. 1996 Jul;1(3):165-7.

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


PMID: 9118344 [PubMed - indexed for MEDLINE]


43. Nat Med. 1995 Mar;1(3):232-6.

Borna disease virus genome transcribed and expressed in psychiatric patients.

Bode L, Zimmermann W, Ferszt R, Steinbach F, Ludwig H.

Department of Virology, Robert Koch-Institut, Berlin, Germany.

Comment in:
    Nat Med. 1995 Mar;1(3):209-10.

Borna disease virus (BDV) is a neurotropic, negative and single-stranded
enveloped RNA virus that persistently infects various domestic animal species.
Infection causes disturbances in behaviour and cognitive functions, but can also 
lead to a fatal neurologic disease. Human infections seemed likely, since serum
antibodies were detected in neuropsychiatric patients. Further proof came from
our discovery that peripheral blood monocytes carry viral antigens. Here, we
present the first data on different viral genomic transcripts in such patients'
cells as well as sequence data of transcripts. Both viral markers seem to
coincide with acute episodes of mood disorders, thus pointing to a new human
virus infection possibly threatening mental health.


PMID: 7585039 [PubMed - indexed for MEDLINE]


44. Nat Med. 1995 Mar;1(3):209-10.

Does Borna disease virus infect humans?

Pyper JM.

Department of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, 
Maryland 21205, USA.

Comment on:
    Nat Med. 1995 Mar;1(3):232-6.

PMID: 7585033 [PubMed - indexed for MEDLINE]


45. Trends Microbiol. 1995 Feb;3(2):64-9.

Borna disease virus: implications for human neuropsychiatric illness.

Lipkin WI, Schneemann A, Solbrig MV.

Dept of Neurology, University of California, Irvine 92717, USA.

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


PMID: 7728387 [PubMed - indexed for MEDLINE]


46. Arch Virol Suppl. 1993;7:159-67.

Borna disease virus infection and affective disorders in man.

Bode L, Ferszt R, Czech G.

Robert Koch-Institute, Department of Virology, Free University Berlin, Federal
Republic of Germany.

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.


PMID: 8219801 [PubMed - indexed for MEDLINE]


47. J Affect Disord. 1993 Jan;27(1):61-8.

Detection of Borna disease virus-reactive antibodies from patients with affective
disorders by western immunoblot technique.

Fu ZF, Amsterdam JD, Kao M, Shankar V, Koprowski H, Dietzschold B.

Wistar Institute of Anatomy, Philadelphia, Pennsylvania.

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.


PMID: 8432962 [PubMed - indexed for MEDLINE]


48. Arch Gen Psychiatry. 1985 Nov;42(11):1093-6.

Borna disease virus. A possible etiologic factor in human affective disorders?

Amsterdam JD, Winokur A, Dyson W, Herzog S, Gonzalez F, Rott R, Koprowski H.

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.


PMID: 3931604 [PubMed - indexed for MEDLINE]


49. Science. 1985 May 10;228(4700):755-6.

Detection of serum antibodies to Borna disease virus in patients with psychiatric
disorders.

Rott R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W, Koprowski H.

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.


PMID: 3922055 [PubMed - indexed for MEDLINE]
no