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Background: Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine., Methods: The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2-3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC)., Results: Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen's d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4-10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL)., Conclusions: Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs., Trial Registration: The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks&#95;web/setLocale&#95;EN.do.

By using neonatal gerbils, we assessed the effect of ribavirin on the proliferation of Borna disease virus (BDV) in the brain. The intracranial inoculation of ribavirin reduced viral propagation in the acutely infected brain, resulting in protection from fatal neurological disorders. We found that the treatment with ribavirin markedly reduces the numbers of OX-42-positive microglial cells, but does not activate expression of Th1 cytokines, in BDV-infected gerbil brains. Our results suggested that ribavirin directly inhibits BDV replication and might be a potential tool for the treatment of BDV infection.

Borna disease virus (BDV) is a nonsegmented, negative-stranded RNA virus that causes neurological diseases in a variety of warm-blooded animal species. Recently, we showed that the nucleoside analog 1-beta-D-arabinofuranosylcytosine (Ara-C) was a potent inhibitor of BDV. This finding was surprising for an RNA virus, since Ara-C is a DNA polymerase inhibitor. Thus, we sought to better define the mechanism of action of Ara-C on BDV. Here, we show that (i) this effect is specific for an arabinoside ring carrying a cytosine base, (ii) it requires phosphorylation of the nucleotide, and (iii) it can be reversed by an excess of cytidine. Using the recently described minigenome assay for BDV, we provide evidence suggesting that Ara-C may act as a competitive inhibitor of the BDV replication complex.

Borna disease virus (BDV) infection in its predominant natural host - horses and sheep - leads to fatal meningoencephalomyelitis. The immune-mediated disease can also be induced experimentally in rats following intra- cerebral BDV infection. Despite a vigorous immune response, BDV persists in the central nervous system (CNS) in surviving rats. However, immunization of rats with BDV-specific T-cells prior to challenge with BDV prevents neurological disease and results in virus clearance from the CNS. To analyze whether interferon gamma (IFNgamma) might contribute to viral clearance in the rat brain, we tested the susceptibility of BDV to the antiviral action of rat IFNgamma using different rat cell lines. Even at high concentrations of IFNgamma, BDV infection of astrocyte and fibroblast cell lines as well as of rat embryo cells could not be inhibited efficiently. Similarly, infection of cultured rat hippocampal slices with BDV was not inhibited by rat IFNgamma. In contrast, de novo BDV infection of monkey kidney cells as well as human oligodendroglial cells was blocked by preincubation with human IFNgamma. Furthermore, IFNgamma reduced the BDV load in persistently BDV-infected human oligodendroglial cells but not in infected rat astrocytes. These data suggest species-specific differences in the susceptibility of BDV to the antiviral action of IFNgamma.

Borna disease virus (BDV) causes neurological diseases in a variety of warm-blooded animal species, possibly including humans. To date, there is no effective treatment against BDV infection. Recently, we reported on the antiviral activity of 1-beta-D-arabinofuranosylcytosine (Ara-C). However, Ara-C's cytotoxic side effects are a major obstacle for its therapeutic use. Herein, we demonstrate that the nucleoside analog 2'-fluoro-2'-deoxycytidine (2'-FdC) exhibits potent antiviral activity against BDV. Importantly, 2'-FdC-associated cytotoxicity is negligible, indicating 2'-FdC as an excellent candidate for the development of antiviral therapy against BDV.

Borna disease virus (BDV) is a nonsegmented, negative-strand RNA virus that causes neurological diseases in a variety of warm-blooded animal species. There is general consensus that BDV can also infect humans, being a possible zoonosis. Although the clinical consequences of human BDV infection are still controversial, experimental BDV infection is a well-described model for human neuropsychiatric diseases. To date, there is no effective treatment against BDV. In this paper, we demonstrate that the nucleoside analog 1-beta-D-arabinofuranosylcytosine (Ara-C), a known inhibitor of DNA polymerases, inhibits BDV replication. Ara-C treatment inhibited BDV RNA and protein synthesis and prevented BDV cell-to-cell spread in vitro. Replication of other negative-strand RNA viruses such as influenza virus or measles virus was not inhibited by Ara-C, underscoring the particularity of the replication machinery of BDV. Strikingly, Ara-C treatment induced nuclear retention of viral ribonucleoparticles. These findings could not be attributed to known effects of Ara-C on the host cell, suggesting that Ara-C directly inhibits the BDV polymerase. Finally, we show that Ara-C inhibits BDV replication in vivo in the brain of infected rats, preventing persistent infection of the central nervous system as well as the development of clinical disease. These findings open the way to the development of effective antiviral therapy against BDV.

The guanosine analogue ribavirin was tested for antiviral activity in two neural cell lines, human oligodendrocytes and rat glia, against Borna disease virus (BDV) strains V and He/80. Ribavirin treatment resulted in lower levels of virus and viral transcripts within 12 h. Addition of guanosine but not adenosine resulted in a profound reduction of the ribavirin effect. Ribavirin appears to be an effective antiviral agent for treatment of BDV infection in vitro. A likely mechanism for its activity is reduction of the intracellular GTP pool, resulting in inhibition of transcription and capping of BDV mRNAs.

It has previously been reported that de novo infection of primary rabbit brain cells with Borna disease virus (BDV) can be blocked with interferon-alpha/beta (IFN), whereas this cytokine has no inhibitory effect on BDV in persistently infected rat lung cells [v. Rheinbaben et al., J. Gen. Virol. (1985) 66: 2,777-2,780]. It remained unclear, however, whether these results indicated that IFN exclusively targets early steps of the BDV replication cycle or whether they simply reflected cell line differences. We now show that BDV replication was effectively inhibited by IFN in both acutely and persistently infected monkey Vero cells. By contrast, IFN had no clear protective effect on either de novo or persistent BDV infections of rat C6 glioblastoma cells. IFN protected C6 cells from the cytopathic effects of vesicular stomatitis virus, excluding the possibility that these cells are devoid of a functional IFN system. In primary rat fibroblasts and in a human oligodendroglial cell line, IFN induced an efficient antiviral state against BDV. These results indicate that BDV is highly susceptible to the antiviral effect of IFN in some cell lines, while others seem to lack undefined components of the IFN system which mediate protection against BDV.

The antiviral effect of amantadine (1-aminoadamantane) was tested in vitro as well as in vivo. Treatment of persistently Borna disease virus (BDV)-infected cell lines of different origin and for various length of time did not result in a general reduction of virus titer or clearance of virus from infected cells. In vivo, rats were treated with amantadine by daily oral application or by use of osmotic pumps, and in both cases treatment was started before infection. Neither route of application of the drug had any influence on the time of onset of disease, on antiviral antibody titers, on virus titer in the brain, on the severity of the inflammatory reaction in the brain, or on the severity of neurological symptoms. These experiments, although revealing negative results and obtained using a virus from a natural case of Borna disease grown after isolation in vitro for a long period of time, should caution from the general use of amantadine as a curative agent against BDV infection as has been implicated recently [Bode et al. (1997) Lancet 349:178-179].

Ribavirin at concentrations from 1 to 10 micrograms/ml exhibited inhibitory effects on transcription of Borna disease virus (BDV) in persistently infected cells. Our present study indicates that ribavirin is a candidate anti-BDV drug.

We have investigated the antiviral activity of amantadine (AD) against Borna disease virus (BDV) in several culture cell systems. We present evidence that AD, in the range 5 to 10 microM, does not have antiviral activity against BDV. Treatment of BDV infected cells with AD for six days caused neither a reduction in the number of infected cells, nor a decrease in steady state levels of BDV RNA or proteins. Moreover, treatment of cells with AD prior infection did not affect BDV multiplication, whereas influenza A virus yield was less than 1% with respect to that obtained in untreated control cells.

Successful inhibition of Borna disease virus (BDV) by amantadine in cultured cells and in an infected human individual has been reported [Bode et al. (1997) Lancet 349: 178-179]. We now found that infection of monkey Vero cells by laboratory strains of BDV was not influenced by amantadine under conditions that reduced the yields of influenza A virus by about 400 fold. Amantadine treatment of Vero cells persistently infected with BDV did not result in reduced viral RNA levels, and application of the drug to persistently infected BALB/c mice had no effect on the concentration of BDV in their brains. Thus, susceptibility to amantadine is not a characteristic of BDV, although it may be observed with certain primary virus isolates.