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Journal of Virology, November 2003, p. 12222-12231, Vol. 77, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.22.12222-12231.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Borna Disease Virus Glycoprotein Is Required for Viral Dissemination in Neurons

Unité des Virus Lents, CNRS URA 1930, Département de Virologie,¹ Unité de Biologie Cellulaire du Noyau, Département Biologie Cellulaire et Infection, Institut Pasteur, Paris,² INSERM U563, CPTP, Toulouse, France,⁴ Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center, Heidelberg, Germany³

Received 20 May 2003/ Accepted 12 August 2003

Borna disease virus (BDV) is a nonsegmented negative-strand RNA virus with a tropism for neurons. Infection with BDV causes neurological diseases in a wide variety of animal species. Although it is known that the virus spreads from neuron to neuron, assembled viral particles have never been visualized in the brains of infected animals. This has led to the hypothesis that BDV spreads as nonenveloped ribonucleoproteins (RNP) rather than as enveloped viral particles. We assessed whether the viral envelope glycoprotein (GP) is required for neuronal dissemination of BDV by using primary cultures of rat hippocampal neurons. We show that upon in vitro infection, BDV replicated and spread efficiently in this system. Despite rapid virus dissemination, very few infectious viral particles were detectable in the culture. However, neutralizing antibodies directed against BDV-GP inhibited BDV spread. In addition, interference with BDV-GP processing by inhibiting furin-mediated cleavage of the glycoprotein blocked virus spread. Finally, antisense treatment with peptide nucleic acids directed against BDV-GP mRNA inhibited BDV dissemination, marking BDV-GP as an attractive target for antiviral therapy against BDV. Together, our results demonstrate that the expression and correct processing of BDV-GP are necessary for BDV dissemination in primary cultures of rat hippocampal neurons, arguing against the hypothesis that the virus spreads from neuron to neuron in the form of nonenveloped RNP.

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