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Journal of Virology, October 2006, p. 9435-9443, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00473-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus BNRF1 Protein Allows Efficient Transfer from the Endosomal Compartment to the Nucleus of Primary B Lymphocytes

R. Feederle,1,2,{dagger} B. Neuhierl,1,{dagger} G. Baldwin,2 H. Bannert,1 B. Hub,1 J. Mautner,3 U. Behrends,3 and H. J. Delecluse1,2*

German Cancer Research Center, Department of Virus Associated Tumours, Heidelberg, Germany,1 Cancer Research UK Institute for Cancer Studies, University of Birmingham, Department of Pathology, Birmingham, United Kingdom,2 Clinical Cooperation Group, Children's Hospital, Hematology-Oncology, Technical University Munich, Munich, Germany3

Received 7 March 2006/ Accepted 18 July 2006

Epstein-Barr virus (EBV) is a tumor virus with marked B lymphotropism. After crossing the B-cell membrane, the virus enters cytoplasmic vesicles, where decapsidation takes place to allow transfer of the viral DNA to the cell nucleus. BNRF1 has been characterized as the EBV major tegument protein, but its precise function is unknown. We have constructed a viral mutant that lacks the BNRF1 gene and report here its in vitro phenotype. A recombinant virus devoid of BNRF1 ({Delta}BNRF1) showed efficient DNA replication and production of mature viral particles. B cells infected with the {Delta}BNRF1 mutant presented viral lytic antigens as efficiently as B cells infected with wild-type or BNRF1 trans-complemented {Delta}BNRF1 viruses. Antigen presentation in B cells infected with either wild-type (EBV-wt) or {Delta}BNRF1 virus was blocked by leupeptin addition, showing that both viruses reach the endosome/lysosome compartment. These data were confirmed by direct observation of the mutant virus in endosomes of infected B cells by electron microscopy. However, we observed a 20-fold reduction in the number of B cells expressing the nuclear protein EBNA2 after infection with a {Delta}BNRF1 virus compared to wild-type infection. Likewise, {Delta}BNRF1 viruses transformed primary B cells much less efficiently than EBV-wt or BNRF1 trans-complemented viruses. We conclude from these findings that BNRF1 plays an important role in viral transport from the endosomes to the nucleus.

* Corresponding author. Mailing address: German Cancer Research Center, ATV-F100, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Phone: 49/6221/424870. Fax: 49/6221/424852. E-mail: h.delecluse{at}dkfz.de.

{dagger} These two authors equally contributed to this work.

Journal of Virology, October 2006, p. 9435-9443, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00473-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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