Alpha/Beta interferon promotes transcription and inhibits replication of borna disease virus in persistently infected cells

Borna disease virus (BDV) is a noncytolytic RNA virus that can replicate in the central nervous system (CNS) of mice. This study shows that BDV multip lication was efficiently blocked in transgenic mice that express mouse alph a-1 interferon (IFN-alpha1) in astrocytes. To investigate whether endogenou s virus-induced IFN might similarly restrict BDV, we used IFNAR(0/0) mice, which lack a functional alpha/beta IFN (IFN-alpha/beta) receptor. As would be expected if virus-induced IFN were important to control BDV infection, w e found that cultured embryo cells of IFNAR(0/0) mice supported viral multi plication, whereas cells from wild-type mice did not. Unexpectedly, however , BDV spread through the CNSs of IFNAR(0/0) and wild-type mice with similar kinetics, suggesting that activation of endogenous IFN-alpha/beta genes in BDV-infected brains was too weak or occurred too late to be effective. Sur prisingly, Northern blot analysis showed that the levels of the most abunda nt viral mRNAs in the brains of persistently infected IFNAR(0/0) mice were about 20-fold lower than those in wild-type mice. In contrast, genomic vira l RNA was produced in about a 10-fold excess in the brains of IFNAR(0/0) mi ce. Human IFN-alpha2 similarly enhanced transcription and simultaneously re pressed replication of the BDV genome in persistently infected Vero cells. Thus, in persistently infected neurons and cultured cells, IFN-alpha/beta a ppears to freeze the BDV polymerise in the transcriptional mode, resulting in enhanced viral mRNA synthesis and suppressing viral genome replication.