Borna disease virus (BDV) can induce severe neurological disorder in Lewis rats and MRL mice. Antiviral CD8 T cells have been shown to be the mediators of disease in these animals. To define molecules involved in the disease process, we performed infection studies in MRL mice lacking either interferon-gamma, a functional Fas/FasL system, chemokine receptor CXCR3, or inducible NO synthase. We further used transgenic MRL mice expressing interferon-gamma-inducible, T cell-attracting chemokine CXCL10 in brain astrocytes. After intracerebral infection with BDV, wild-type and mutant mice developed CD8 T cell responses and neurological disease at similar frequency and with similar kinetics, suggesting that these factors are not required for initiation and maintenance of the immunopathological process. Similarly, the course of disease could not be altered by treating infected MRL mice or Lewis rats with the drug L-N(6)-(1-iminoethyl)-lysine (L-NIL) that specifically blocks the activity of the inducible NO synthase. We therefore have excluded a number of important factors that have been demonstrated to be crucial in the pathogenesis of a broad number of pathologic conditions. Thus, BDV-induced disease may not result from the action of a single dominant T cell-dependent effector molecule. Disease rather reflects a combined influence of several as yet undefined factors from CD8 T cells.