Borna disease virus infection, a human mental-health risk

Abstract

This article focuses on human Borna disease virus (BDV) infections, most notably on the development of valid diagnostic systems, which have arisen as a major research issue in the past decade. The significance of a novel modular triple enzyme-linked immunosorbent assay that is capable of specifically measuring anti-BDV antibodies as well as major structural proteins N (p40) and P (p24) in the blood, either as free antigens in the plasma or as antibody-bound circulating immune complexes (CICs), is explained. The impact of CICs and plasma antigen, which indicate periods of antigenemia in the course of BDV infection, along with other infection markers that are still in use is discussed. The review further provides new insight into possible links of BDV to human diseases, summarizing cross-sectional and longitudinal data which correlate acute depression with the presence and amount of antigen and CICs. Moreover, BDV prevalence in healthy people is reevaluated, suggesting that this was previously underestimated. Antiviral efficacy of amantadine, in vivo and in vitro, is outlined as well, with emphasis on wild-type (human and equine) versus laboratory strains. Finally, the pros and cons of the association of BDV with human disease, as detailed in the literature, are critically discussed and related to our data and concepts. This article supports existing correlative evidence for a pathogenic role of BDV infection in particular human mental disorders, in analogy to what has been proven for a variety of animal species.

FIG. 1.

Prevalence and duration of BDV antigen markers in patients with major depressive disorder or bipolar disorder during acute depression. Prevalence of three antigen markers, cAg (antigen in PBMCs), pAg (antigen in plasma), and CICs (circulating immune complexes) in representative age- and gender-matched major depressive disorder and bipolar disorder patient cohorts versus healthy controls; for plasma antigen and CIC, the prevalence of patients with large amounts (plasma antigen high, CIC high) is shown separately (data modified from Table 2 in reference 8). Note that only severely depressed patients showed high plasma antigen values.

FIG. 2.

Duration of antigenemia in seven individual patients with acute severe depression (these patients were selected from group I in Table 2 of reference 8) presenting with high levels of plasma antigen (pAg) over a period of several weeks.

FIG. 3.

BDV CIC levels in a patient with chronic depression. Six-month follow-up of a representative patient (male, age 59 years), showing continuously changing CIC values as the predominant infection marker (reprinted with slight modifications from reference with permission). See Fig. 1 legend for abbreviations. Ab, antibodies. The linear regression line for CIC values shows almost no change over 6 months.

FIG. 4.

Scheme of mood disorders. This classification is based on DSM IV; shadowed frames indicate those disorders (major depressive disorder [MDD] and bipolar [BP] disorders I and II; DSM IV, no. 296.xx), for which almost all patients were found to be infected (>90%) as deduced from the presence of CICs in blood when tested during an acute depressive episode. NOS, not otherwise specified.

FIG. 5.

BDV infection in chronic fatigue syndrome and antiviral treatment. Five-year follow-up of a chronic fatigue syndrome patient with high initial antigenemia, showing a slow but continuous decrease (see linear regression line) of plasma antigen during amantadine treatment started in month 14. This was paralleled by partial but sustained clinical improvement, i.e., expressed by restored ability for daily work but still with reduced energy compared to previous skills. For abbreviations, see the legends to Fig. 1 and 3.

FIG. 6.

In vitro antiviral treatment of BDV-infected human oligodendroglia cells. Persistently infected oligodendroglia cells were split every 3 days and maintained in medium containing amantadine (0.4 μg/ml, therapeutic blood level doses). At the indicated time points, infectivity in these cells was titered on young rabbit brain cells (for details, see reference 7). Note the time-dependent infectivity decrease for the sensitive wild-type strains, two human isolates (Hu-H1 [8] and Hu-HUSA1, isolated from an American chronic fatigue syndrome patient [9]), and one equine isolate (Equ-Cres, isolated from PBMCs of a horse with Borna disease) versus stable titers in two resistant laboratory strains (strains V and Dessau).