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 multiplication was efficiently blocked in transgenic mice that express mouse alpha-1 interferon (IFN-alpha1) in astrocytes. To investigate whether endogenous 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, we found that cultured embryo cells of IFNAR(0/0) mice supported viral multiplication, 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. Surprisingly, Northern blot analysis showed that the levels of the most abundant 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 viral RNA was produced in about a 10-fold excess in the brains of IFNAR(0/0) mice. Human IFN-alpha2 similarly enhanced transcription and simultaneously repressed replication of the BDV genome in persistently infected Vero cells. Thus, in persistently infected neurons and cultured cells, IFN-alpha/beta appears to freeze the BDV polymerase in the transcriptional mode, resulting in enhanced viral mRNA synthesis and suppressing viral genome replication.
Staeheli
P
P
Department of Virology, University of Freiburg, D-79104 Freiburg, Germany. staeheli@ukl.uni-freiburg.de
Sentandreu
M
M
Pagenstecher
A
A
Hausmann
J
J
D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000821:virology; D001890:Borna Disease / Q000821:virology*; D001891:Borna disease virus / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000821:virology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D016679:Genome, Viral; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012367:RNA, Viral / Q000032:analysis; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D019076:Transgenes; D014709:Vero Cells; D014779:Virus Replication
D016898:Interferon-alpha; D012367:RNA, Viral; D017471:Receptors, Interferon; D016899:Interferon-beta