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Journal of Virology, February 2008, p. 1739-1747, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.01723-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Latent Membrane Protein 2B Regulates Susceptibility to Induction of Lytic Epstein-Barr Virus Infection{triangledown}

Markus P. Rechsteiner,1 Christoph Berger,1 Ludwig Zauner,1 Jürg A. Sigrist,1 Matthias Weber,1 Richard Longnecker,2 Michele Bernasconi,1,{dagger} and David Nadal1*,{dagger}

Experimental Infectious Diseases and Cancer Research, Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, CH-8032 Zurich, Switzerland,1 Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 606112

Received 8 August 2007/ Accepted 24 November 2007

The B-lymphotropic Epstein-Barr virus (EBV) encodes two isoforms of latent membrane protein 2 (LMP2), LMP2A and LMP2B, which are expressed during latency in B cells. The function of LMP2B is largely unknown, whereas LMP2A blocks B-cell receptor (BCR) signaling transduction and induction of lytic EBV infection, thereby promoting B-cell survival. Transfection experiments on LMP2B in EBV-negative B cells and the silencing of LMP2B in EBV-harboring Burkitt's lymphoma-derived Akata cells suggest that LMP2B interferes with the function of LMP2A, but the role of LMP2B in the presence of functional EBV has not been established. Here, LMP2B, LMP2A, or both were overexpressed in EBV-harboring Akata cells to study the function of LMP2B. The overexpression of LMP2B increased the magnitude of EBV switching from its latent to its lytic form upon BCR cross-linking, as indicated by a more-enhanced upregulation and expression of EBV lytic genes and significantly increased production of transforming EBV compared to Akata vector control cells or LMP2A-overexpressing cells. Moreover, LMP2B lowered the degree of BCR cross-linking required to induce lytic EBV infection. Finally, LMP2B colocalized with LMP2A as demonstrated by immunoprecipitation and immunofluorescence and restored calcium mobilization upon BCR cross-linking, a signaling process inhibited by LMP2A. Thus, our findings suggest that LMP2B negatively regulates the function of LMP2A in preventing the switch from latent to lytic EBV replication.

* Corresponding author. Mailing address: Experimental Infectious Diseases and Cancer Research, Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zurich, Zurich, Switzerland. Phone: 41-44-266-7250. Fax: 41-44-266-7082. E-mail: david.nadal{at}kispi.uzh.ch

{triangledown} Published ahead of print on 5 December 2007.

{dagger} Contributed equally.

Journal of Virology, February 2008, p. 1739-1747, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.01723-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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