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Journal of Virology, May 2009, p. 4297-4307, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02321-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Protein X of Borna Disease Virus Inhibits Apoptosis and Promotes Viral Persistence in the Central Nervous Systems of Newborn-Infected Rats {triangledown}

Marion Poenisch,{dagger} Nils Burger,{ddagger} Peter Staeheli, Georg Bauer, and Urs Schneider*

Department of Virology, University of Freiburg, D-79104 Freiburg, Germany

Received 6 November 2008/ Accepted 31 January 2009

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-XA6A7) failed to block apoptosis in C6 cells. Furthermore, Lewis rats neonatally infected with BDV-XA6A7 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-XA6A7-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.

* Corresponding author. Mailing address: Department of Virology, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany. Phone: 49-761-203-6222. Fax: 49-761-203-5053. E-mail: urs.schneider{at}uniklinik-freiburg.de

{triangledown} Published ahead of print on 11 February 2009.

{dagger} Present address: Department of Molecular Virology, University of Heidelberg, D-69120 Heidelberg, Germany.

{ddagger} Present address: Clinical Cancer Research Center, University Hospital Basel, CH-4031 Basel, Switzerland.

Journal of Virology, May 2009, p. 4297-4307, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02321-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Poenisch, M., Wille, S., Schneider, U., Staeheli, P. (2009). Second-site mutations in Borna disease virus overexpressing viral accessory protein X. J. Gen. Virol. 90: 1932-1936 [Abstract] [Full Text]  


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