Neutralizing Antibodies in Persistent Borna Disease Virus Infection: Prophylactic Effect of gp94-Specific Monoclonal Antibodies in Preventing Encephalitis

Abstract

Borna disease virus (BDV) infection triggers an immune-mediated encephalomyelitis and results in a persistent infection. The immune response in the acute phase of the disease is characterized by a cellular response in which CD8؉ T cells are responsible for the destruction of virus-infected brain cells. CD4 ؉ T cells function as helper cells and support the production of antiviral antibodies. Antibodies generated in the acute phase of the disease against the nucleoprotein and the phosphoprotein are nonneutralizing. In the chronic phase of the disease, neutralizing antibodies directed against the matrix protein and glycoprotein are synthesized. In the present work, the biological role of the neutralizing-antibody response to BDV was further investigated. By analyzing the blood of rats infected intracerebrally with BDV, a highly neurotropic virus, nucleic acid could be detected between 30 and 50 days after infection. Neutralizing antibodies were found between 60 and 100 days after infection. Furthermore, we produced hybridomas secreting BDV-specific neutralizing monoclonal antibodies. These antibodies, directed against the major glycoprotein (gp94) of BDV, were able to prevent Borna disease if given prophylactically. These data suggest that the late appearance of BDV-specific neutralizing antibodies is due to the presence of BDV in the blood of chronically infected rats. Furthermore, these antibodies have the potential to neutralize the infectious virus when given early, which is an important finding with respect to the development of a vaccine.

Open Reading Frame III of Borna Disease Virus Encodes a Nonglycosylated Matrix Protein

“…This false conclusion has serious consequences: the misinterpretation of p16 as an N-glycosylated matrix protein, the occurrence of p16 on the virus surface, and the misleading interpretation that antibodies to p16 have neutralizing activity (14,15,(30)(31)(32). A recent publication (11) shows that neutralizing activity for BDV infection was found only with monoclonal antibodies raised against gp94, not with those against p16, which were raised against recombinant BDV proteins. Moreover, previous immunocytochemical investigations which used antibodies directed to carbohydrate-contaminated p16 need to be reexamined.…”

Epidemiology and host spectrum of Borna disease virus infections

“…Although the relevance of neutralizing antibodies is difficult to determine in natural infections, neutralizing antibodies against the major glycoprotein prevent infection and encephalitis in laboratory rats if administered prophylactically (Furrer et al, 2001b), but not if administered simultaneously with the virus (Stitz et al, 1998). Immunosuppressed rats mount a humoral, but not a cellular immune response (Stitz et al, 1998).…”

High-Dose Borna Disease Virus Infection Induces a Nucleoprotein-Specific Cytotoxic T-Lymphocyte Response and Prevention of Immunopathology

“…These results show that 10 2 FFU of BDV-MDCK induces disease while infection with 10 4 FFU apparently represents a breaking point, where some animals develop disease and others control the virus and do not develop BD. This finding also indicates differences among BDV isolates that possibly depend on their passage history in vitro; BDV has been cultured in MDCK cells for more than 20 years (12), whereas it has been passaged in CRL1405 cells only for a short time (9). Infection of rats with HD BDV-CRL or BDV-MDCK (10 6 FFU) resulted in an early induction of the humoral immune response.…”

“…Control of a virus infection usually is due to the activity of the humoral and/or cellular arm of the immune system. Only recently has it been demonstrated that neutralizing glycoproteinspecific antibodies can have a prophylactic effect in experimental BD (9). However, apart from the early induction of nonneutralizing antibodies against the nucleoprotein and the phosphoprotein, no neutralizing antibodies were found in sera from BDV-CRL-or BDV-MDCK-infected rats.…”

“…CD8 ϩ T cells represent the effector cell population, exhibiting antigen specificity for the nucleoprotein p40, specifically for the peptide ASYAQMTTY, in the Lewis rat (23-25, 27, 32). No evidence has been presented that antibodies might contribute to neuropathology, although neutralizing antibodies apparently control virus tropism and can prevent the spread of virus from peripheral infection sites to the CNS (9,11,34).…”