Protein X of Borna disease virus inhibits apoptosis and promotes viral persistence in the central nervous systems of newborn-infected rats.
Borna disease virus (BDV) is a neurotropic member of the order Mononegavirales with noncytolytic replication and obligatory persistence in cultured cells and animals. Here we show that the accessory protein X of BDV represents the first mitochondrion-localized protein of an RNA virus that inhibits rather than promotes apoptosis induction. Rat C6 astroglioma cells persistently infected with wild-type BDV were significantly more resistant to death receptor-dependent and -independent apoptotic stimuli than uninfected cells or cells infected with a BDV mutant expressing reduced amounts of X. Confocal microscopy demonstrated that X colocalizes with mitochondria and expression of X from plasmid DNA rendered human 293T and mouse L929 cells resistant to apoptosis induction. A recombinant virus encoding a mutant X protein unable to associate with mitochondria (BDV-X(A6A7)) failed to block apoptosis in C6 cells. Furthermore, Lewis rats neonatally infected with BDV-X(A6A7) developed severe neurological symptoms and died around day 30 postinfection, whereas all animals infected with wild-type BDV remained healthy and became persistently infected. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining revealed a significant increase in the number of apoptotic cells in the brain of BDV-X(A6A7)-infected animals, whereas the numbers of CD3(+) T lymphocytes were comparable to those detected in animals infected with wild-type BDV. Our data thus indicate that inhibition of apoptosis by X promotes noncytolytic viral persistence and is required for the survival of cells in the central nervous system of BDV-infected animals.
Poenisch
Marion
M
Department of Virology, University of Freiburg, Freiburg, Germany.
Burger
Nils
N
Staeheli
Peter
P
Bauer
Georg
G
Schneider
Urs
U
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn / Q000821:virology; D017209:Apoptosis; D001890:Borna Disease / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D001891:Borna disease virus / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism* / Q000821:virology*; D002522:Chlorocebus aethiops; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D051381:Rats; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D015534:Trans-Activators