This is a very exciting time for Borna disease virus (BDV) research because many questions still linger unanswered about the puzzle of its pathogenesis in humans.  However, unlike most other viruses which were discovered and analyzed decades ago, the incredible pace and level of modern day technology has allowed researchers to make gigantic strides in one short year.  In 1999, our understanding of this mysterious virus has progressed from stubborn skepticism to target cell localization and pathogenesis to treatment options.  The millennium closed on Borna with the following insights:

IS IT HUMAN...IS IT NOT?  WHAT EXACTLY DO WE HAVE ON OUR HANDS ...AND GLASSWARE?

A review letter submitted by Martin Schwemmie, et al presented a very skeptical view of human BDV infection.  This research team asserts that the staggering genetic similarity between human bornavirus RW98 and the rat-adapted laboratory strain of bornavirus is not coincidental.   They suggest that the two genomes are too homologous to be unrelated and suggest that RW98 represents not a human bornavirus strain but a laboratory contamination of human specimens with the laboratory viral strain.
Schwemmie, M, et al.  "Sequence similarities between human bornavirus isolates and laboratory strains question human origin." The Lancet, v354, Dec. 4, 1999.

However, another research team answered Schwemmie's skepticism with an isolation of a human-specific BDV strain that is not genetically identical to the lab rat strain.  Planz, et al found that granulocytes represent the major if not the sole cell type harboring  BVD-specific nucleic acid in human blood.  The virus isolated from these cells is genetically different enough to negate the assertion that human bornavirus does not exist, as proposed by Schwemmie.
Planz, O, et al.  "Pathogenesis of borna disease virus: granulocyte fractions of psychiatric patients harbor infectious virus in the absence of antiviral antibodies".  Journal of Virology, 1999 Aug, 73(8):6251-6.

DOES IT DRIVE YOU CRAZY ... OR DO YOU DRIVE IT CRAZY?

Still, because bornavirus remains new on the research market, its clinical correlation to psychiatric disorders in humans is difficult to prove.  It was determined a few years ago that BDV is present in the brains of a significant portion of patients exhibiting behavioral anomalies.  But does the virus cause anomalies such as severe depression and schizophrenia or is its presence a mere coincidence?  Scientists have made significant efforts to resolve this enigma.

In an attempt to determine the frequency of persistent BDV in the human central nervous system, Czygan et al analyzed a large collection of autopsy brain samples.  Reverse transcription-nested PCR reaction  was performed to detect BVD RNA.  Surprisingly, only 3 samples from persons with psychiatric disorders and prominent hippocampal degeneration exhibited the presence of viral RNA.  Another 86 samples from patients with various psychiatric disorders (including schitzophrenia, affective disorders, etc.) were negative for BDV.  The study convinced the team thatpersistent BDV infections are quite rare in humans, although it may be associated with hippocampal degeneration.
Czygan, M, et al.  "Borna disease virus in human brains with a rare form of hippocampal degeneration but not in brains of patients with common neuropsychiatric disorders." Journal of Infectious Diseases, 1999 Nov, 180(5):1695-9.

In contrast to the above article,  series of studies by Chen et al have confirmed that Taiwanese patients with schitzophrenia and depression do, in fact, have a higher prevalence of BDV-specific antibodies and BDV transcripts than do controls.   This provides a positive association between the virus and psychiatric disorders.   Interestingly, the team also analyzed blood samples of patients' family members and mental health workers and determined that they, too, exhibit a significantly higher rate of BDV infection than the control population.   This provides the evidence of human-to-human transmission of Borna disease virus.
Chen, CH, et al.  "High seroprevalence of Borna virus infection in schitzophrenic patients, family members and mental health workers in Taiwan."  Molecular Psychiatry, 1999 Jan, 4(1):33-8.

The same research team later isolated BDV RNA from the peripheral blood cells of 10 out of 74 schizophrenic patients (or 14%), as compared to only one infected person out of 69 controls.   Furthermore, seven out of 45 mental health workers were found to be positive for BDV, representing a 15% infection rate, as compared to 1.4% rate among the control subjects.  These quantitative data suggest that Borna disease virus may, indeed, contribute to the pathogenesis of schitzophrenia.
Chen, CH, et al.  "Detection of Borna disease virus RNA from peripheral blood cells in schitzophrenic patients and mental health workers."  Molecular Psychiatry, 1999 Nov, 4(6):566-71.

NOW THAT WE KNOW WHAT IT IS, WHAT DO YOU SUGGEST WE DO ABOUT IT?

Several drugs are now being studied and tested as potential antiviral agents for Borna disease virus.  Currently, most of these drugs are still being tested on laboratory animals, but who knows what another year will bring...

A guanosine analog ribavirin has been shown to inhibit viral activity in vitro.  Twelve hours following a ribavirin treatment, the Jordan et al team found a significant reduction in both the level of virus and viral transcripts.  Ribavirin acts to reduce intracellular GTP pool, thus inhibiting transcription and capping of BDV mRNA.
Jordan, I, et al.  "Inhibition of Borna disease virus replication by ribavirin." Journal of Virology, 1999 Sep, 73(9):7903-6.

Interferon-alpha (IFN) is also proving to be a highly effective retroviral drug for BDV.  Hallensleben, et al found that BDV replication cycle was significantly blocked by IFN in infected monkeys, although this antiviral effect was not seen in all cell lines.
Hallensleben, W.  "Inhibition of Borna disease virus multiplication by interferon:cell differences in susceptibility."  Archives of Virology, 1999, 144(6):1209-16.

Amantadinesulfate is a useful antiviral agent in the treatment of a wide spectrum of viral infections.  However, it has also been reported as producing some mild antidepressive effects.  Research carried out by Ferszt, et al tested this phenomenon and the results are very promising for anti-BDV treatment.  In a clinical study, 30 depressed patients with various states of BDV infection were given oral amantadine for 8 to 12 weeks.  The treatment produced antidepressive response in 19 of the 30 patients, suggesting, once again, that the depression was associated with a viral infection which is susceptible to the antiviral properties of amantadine.
Ferszt, R.  "Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection".  Pharmacopsychiatry, 1999 Jul, 32(4):142-7.