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Journal of Virology, March 2005, p. 3703-3712, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3703-3712.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

BFRF1 of Epstein-Barr Virus Is Essential for Efficient Primary Viral Envelopment and Egress

Antonella Farina,1 Regina Feederle,2 Salvatore Raffa,3 Roberta Gonnella,1 Roberta Santarelli,1 Luigi Frati,1 Antonio Angeloni,1 Maria Rosaria Torrisi,1,3,4 Alberto Faggioni,1* and Henri-Jacques Delecluse2

Istituto Pasteur Fondazione Cenci-Bolognetti, Dipartimento di Medicina Sperimentale e Patologia, Università di Roma La Sapienza,1 Azienda Ospedaliera Sant'Andrea,3 Istituto Dermatologico Santa Maria e San Gallicano, IRCCS, Rome, Italy,4 Department of Virus Associated Tumours, German Research Cancer Centre, Heidelberg, Germany2

Received 14 June 2004/ Accepted 3 December 2004

The molecular mechanisms that underlie maturation and egress of Epstein-Barr virus (EBV) virions are only partially characterized. We have recently shown that the BFRF1 gene, the EBV positional homolog of herpes simplex virus type 1 and pseudorabies virus UL34, is expressed early during EBV lytic replication and that it is found predominantly on the nuclear membrane (A. Farina, R. Santarelli, R. Gonnella, R. Bei, R. Muraro, G. Cardinali, S. Uccini, G. Ragona, L. Frati, A. Faggioni, and A. Angeloni, J. Virol. 74:3235-3244, 2000). These data suggest that the BFRF1 protein might be involved in viral primary envelopment. To precisely determine the function of this protein, we have constructed an EBV mutant devoid of the BFRF1 gene (BFRF1-KO). 293 cells carrying BFRF1-KO showed no differences in comparison with wild-type EBV in terms of DNA lytic replication or expression of late viral proteins upon induction of the lytic cycle. However, binding assays and infection experiments using cell lines or human cord blood lymphocytes showed a clear reduction in the viral mutant titers. Complementation experiments with BFRF1-KO and a BFRF1 expression vector restored viral titers to levels similar to those for the wild-type control, showing that the modifications that we introduced were limited to the BFRF1 gene. Electron microscopic observations showed that the reduction in viral titers was due to sequestration of EBV nucleocapsids in the nuclei of lytically induced cells. This suggests that BFRF1 is involved in transport of the maturing virion across the nuclear membrane. This hypothesis was further supported by the observation that BFRF1 is present in maturing intracellular virions but not in their extracellular counterparts. This implies that BFRF1 is a key protein for EBV maturation.

* Corresponding author. Mailing address: Dipartimento di Medicina Sperimentale e Patologia, Università di Roma La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy. Phone: 3906-4461500. Fax: 3906-4468450. E-mail: alberto.faggioni{at}uniroma1.it.

Journal of Virology, March 2005, p. 3703-3712, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3703-3712.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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