Bernard Dixon

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Borna Virus—a Shift in Mood?

Over 200 years after the first published description of Borna disease, the virus responsible for this condition in horses is coming under increasing suspicion as a cause of mood disorders in humans

Bernard Dixon

With a little help from psychiatrists, virologists may be about to solve a longstanding conundrum: does Borna virus play a major role in conditions such as bipolar disorder (manic-depressive psychosis) and obsessional-compulsive neurosis? That prospect, with clear implications for treatment, proved to be one of the major talking points during the recent annual meeting of the Society for General Microbiology (SGM) in Edinburgh, Scotland.

The story actually began as long ago as 1785 with the work of an extraordinary Danish polymath, Peter Christian Abildgaard. Although qualified primarily as a veterinarian and physician, Abildgaard made important advances in fields as diverse as geology, parasitology, chemistry, and physiology.

Alongside these diverse contributions, Abildgaard published the first scientific description of a horse disease which had probably been present in Germany and Switzerland for centuries. Abildgaard's work led to the condition being termed Borna disease, because of its endemic occurrence in horses around Borna near Leipzig, Germany. Much more recently, the disease has been found in cattle, sheep, goats, ostriches, and monkeys. Five years ago it was reported in cats for the first time.

In its acute form in horses and other susceptible animals, Borna disease is manifested as a meningoencephalomyelitis, causing shaking and an unsteady gait. Afflicted animals tend to run into obstacles and (as far as humans can judge) become depressed. The infection is usually fatal.

A nonpurulent encephalomyelitis, Borna disease particularly affects the gray matter of the cerebral hemispheres and the brainstem. Animals are infected either intranasally or through the gut, as when horses drink contaminated water. The infection travels through both the central nervous system and the bloodstream. Infectious virus can be released through the urine and nasal mucosae.

Until a few years ago, the causative agent tended to be described as a suspected or uncharacterized virus, sometimes as a "slow virus." Over the past decade, however, Hanns Ludwig of the Free University of Berlin and Liv Bode of the Robert-Koch Institute in Berlin have pinpointed a novel RNA virus as the cause of the condition. It is genetically stable, and isolates from different species show high levels of sequence conservation. However, viruses with specific genotypes also seem to adapt to particular hosts.

Speaking at Heriot-Watt University in Edinburgh, Scotland, during the SGM meeting, Liv Bode pulled together the strands of evidence which now indict Borna disease virus (BDV) as a likely, though not yet certain, cause of psychiatric illness in humans. The initial advance was made about 15 years ago by her senior colleague Rudi Rott, working at Justus-Liebig University in Giessen, Germany, in collaboration with Hilary Koprowski at the Wistar Insitute in Philadephia, Pa., and coworkers in Ulm, Germany.

In view of the behavioral and central nervous system effects of BDV in experimental animals, they wondered whether it might be involved in human mental conditions too. So they looked for specific antibodies in sera from nearly 1,000 subjects with emotional and depressive disorders. They compared the patients, in Philadelphia and two different regions of Germany (Giessen and Wurzburg), with 200 healthy volunteers. The results were no more than suggestive: there were BDV antibodies in 16 of the patients but in none of the normal subjects. One interesting finding was that more than 4% of the patients in Philadelphia were positive for the antibodies, as compared with less than 1% of those in Giessen and Wurzburg. The researchers suggested that this might be due to the more heterogeneous nature of the patient population in Germany.

As Liv Bode reported in Edinburgh, groups throughout the world have now found BDV-specific antibodies in individuals with psychiatric disease. Although these have usually been demonstrated in low titers, there has been a consistently significant difference between their presence in 10-15% of patients and in only 1-3% of healthy controls. Moreover, when investigators have monitored subjects over the long term, the prevalence of antibodies has risen to 30%, possibly reflecting reactivation of a persistent infection over time.

Stronger evidence came from Liv Bode and her colleagues a few years ago when they were the first to isolate BDV itself from individuals with mood disorders. They found the virus in peripheral blood mononuclear cells from 3 out of 23 psychiatric inpatients—two with bipolar disorder—and one with obsessional-compulsive neurosis.

There was also an indication that productive virus infection was related to the progression of the disease, since infectious virions (assessed by infection of rabbits) were isolated from the blood cells during acute episodes of the mood disorders. It is, of course, possible that it was the onset of these acute phases that activated a persistent, latent BDV infection.

Another strand of suggestive, yet still ambiguous, evidence concerns new infection markers. The Berlin group has, for example, developed a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) to demonstrate plasma antigen in about 20% of 1,000 serum samples from severely depressed patients. The antigen often appeared at the beginning of the period of depression, remained constant for several days, and then progressively declined.

Bode and her collaborators have also detected circulating immune complexes (CICs), sometimes at high levels, in BDV-infected humans and animals. Their initial work on subjects with more or less clinically well-defined major depression showed much higher percentages of positives as compared with other markers. In work not yet published, they have found CICs as evidence of infection in 100% of patients with severe depression, but in only 25% of individuals in control populations. The levels of CICs also correlated with the severity of the symptoms.

Although not conclusive, findings of this sort appear more compelling when considered alongside those that have emerged from antiviral therapy. Amantadine sulfate in particular not only reduces the infectivity of BDV isolates in tissue culture, but also helps human patients. The first case treated by Bode and her group was a woman with a major mood disorder (plus Parkinson's disease), whose depression abated following amantadine therapy.

"Over the last two years" Bode reports, "independent clinical trials on moderately depressed outpatients in Berlin and Hanover have shown that antiviral therapies are an alternative treatment for patients suffering from activated BDV. In two open trials, a clinical responder rate of approximately 70% has supported the view that infected patients had a clear benefit from this treatment." A recently completed 1.5-year double-blind placebo study is now in the process of statistical evaluation.

Discussing the relevance of BDV for humans only last year in The Invisible Enemy, A Natural History of Viruses (Oxford University Press), Dorothy Crawford wrote: "Clearly, it is important to develop a reliable test for this virus and sort the matter out forever." The techniques evolved by Liv Bode and her coworkers in Berlin have already gone some way toward answering that plea. Yet the story of BDV and human mental illness remains incomplete.

Koch's postulates certainly remained unsatisfied. But so too do a range of wider questions. What are the true prevalence rates for infection in human populations? Do humans acquire (and transmit?) the infection in the same way as horses and other animals? What is or are the natural reservoir(s) for the virus? And (not quite the same question) what is or are the source(s) of infection for humans? Is BDV a true zoonosis?

These are all questions that would have attracted Peter Abildgaard. He was, after all, the first person ever to demonstrate the life cycle of a parasite (a tapeworm) in two different types of animal (birds and fish). He would certainly have relished this challenge in humans and horses.