Borna disease virus (BDV) induces a nonpurulent CD4-and CD8-T-cell-dependent meningoencephalitis in susceptible animals. Upon intracerebral infection, BDV replicates in the mouse central nervous system (CNS),but only a few mouse strains develop neurological disorder. The antiviral T cells appear to suppress BDV replication by a noncytolytic mechanism. Since BDV does not replicate in standard mouse cell cultures, the putative role of gamma interferon (IFN-␥) in virus control could not be tested experimentally. Here, we report that mouse organotypic slice cultures can be used to elucidate the complex interactions of BDV, the CNS, and the immune system. We show that BDV replicated in various cell types of mouse cerebellar slice cultures in vitro. In infected slice cultures, a moderate upregulation of the chemokine genes CCL5 and CXCL10 was observed, while expression of various neural genes as well as other chemokine and cytokine genes was not altered. IFN-␥ inhibited the multiplication of BDV in cerebellar and hippocampal slice cultures in a dosedependent manner. However, while complete suppression of BDV was observed in cerebellar slice cultures, inhibition was incomplete in hippocampal slice cultures. Kinetic studies indicated that IFN-␥ protects noninfected cells from infection rather than clearing the virus from infected cells. These results demonstrate that BDV can replicate in cultured neural cells of the mouse if organ integrity is well preserved. They further show that IFN-␥ is a powerful inhibitor of BDV in the absence of blood-borne leukocytes in mouse cerebellar slice cultures.Borna disease virus (BDV) is a nonsegmented, negativestranded RNA virus that can persistently infect the central nervous system (CNS) of a variety of animal species (for a review, see reference 21), which may then develop a severe nonpurulent meningoencephalitis (9,13,17). Natural infection with BDV occurs in horses, sheep, and other species (21). Although natural BDV infection of mice has not been reported, BDV can replicate in the mouse CNS after intracerebral infection (10, 11). However, most mouse strains are resistant to BDV-induced disease, and only mice of few strains, such as MRL, develop neurological disorder following infection with BDV (10, 11). In MRL mice, the antiviral CD8 T cells recognize a single immunodominant epitope located in the BDV nucleoprotein (20). These cells mediate both antiviral protection and neurological disease depending on whether they arrive in the brain before or after BDV has disseminated widely through the organ. Because the antiviral response toward BDV is unaltered in mutant MRL mice lacking perforin or lacking a functional fas system, it appears that the antiviral T cells employ as-yet-undefined, noncytolytic mechanisms to target BDV in infected cells (12). Using knockout and transgenic mice, we showed that alpha interferon (IFN-␣) has the potential to control BDV in the CNS (22). However, the IFN-␣ and IFN-␤ genes are barely expressed in response to BDV infection, indicating that these cyto...