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Journal of Virology, January 2005, p. 841-852, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.841-852.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus gp42 Is Posttranslationally Modified To Produce Soluble gp42 That Mediates HLA Class II Immune Evasion

Maaike E. Ressing,1* Daphne van Leeuwen,1 Frank A. W. Verreck,2 Sinéad Keating,3 Raquel Gomez,4 Kees L. M. C. Franken,2 Tom H. M. Ottenhoff,2 Melanie Spriggs,5 Ton N. Schumacher,4 Lindsey M. Hutt-Fletcher,6 Martin Rowe,3 and Emmanuel J. H. J. Wiertz1

Departments of Medical Microbiology,1 Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden,2 Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands,4 Section of Infection and Immunity, College of Medicine, University of Wales, Cardiff, United Kingdom,3 Amgen Corp., Seattle, Washington,5 Department of Microbiology and Immunology, Louisiana State University Health Science Center, Shreveport, Louisiana6

Received 31 March 2004/ Accepted 5 September 2004

Epstein-Barr virus (EBV) resides as a persistent infection in human leukocyte antigen (HLA) class II+ B lymphocytes and is associated with a number of malignancies. The EBV lytic-phase protein gp42 serves at least two functions: gp42 acts as the coreceptor for viral entry into B cells and hampers T-cell recognition via HLA class II molecules through steric hindrance of T-cell receptor-class II-peptide interactions. Here, we show that gp42 associates with class II molecules at their various stages of maturation, including immature {alpha}ßIi heterotrimers and mature {alpha}ß-peptide complexes. When analyzing the biosynthesis and maturation of gp42 in cells stably expressing the viral protein, we found that gp42 occurs in two forms: a full-length type II membrane protein and a truncated soluble form. Soluble gp42 is generated by proteolytic cleavage in the endoplasmic reticulum and is secreted. Soluble gp42 is sufficient to inhibit HLA class II-restricted antigen presentation to T cells. In an almost pure population of Burkitt's lymphoma cells in the EBV lytic cycle, both transmembrane and soluble forms of gp42 are detected. These results imply that soluble gp42 is generated during EBV lytic infection and could contribute to undetected virus production by mediating evasion from T-cell immunity.

* Corresponding author. Mailing address: Department of Medical Microbiology, Leiden University Medical Center, Bldg. 1 E4, P P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31 71 526 6797. Fax: 31 71 526 6761. E-mail: m.ressing{at}lumc.nl.

Journal of Virology, January 2005, p. 841-852, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.841-852.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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