γ1-Herpesviruses such as Epstein-Barr virus (EBV) have a unique ability to amplify virus loads in vivo through latent growth-transforming infection. Whether they, like α- and β-herpesviruses, have been driven to actively evade immune detection of replicative (lytic) infection remains a moot point. We were prompted to readdress this question by recent work (Pudney, V.A., A.M. Leese, A.B. Rickinson, and A.D. Hislop. 2005. J. Exp. Med. 201:349–360; Ressing, M.E., S.E. Keating, D. van Leeuwen, D. Koppers-Lalic, I.Y. Pappworth, E.J.H.J. Wiertz, and M. Rowe. 2005. J. Immunol. 174:6829–6838) showing that, as EBV-infected cells move through the lytic cycle, their susceptibility to EBV-specific CD8+ T cell recognition falls dramatically, concomitant with a reductions in transporter associated with antigen processing (TAP) function and surface human histocompatibility leukocyte antigen (HLA) class I expression. Screening of genes that are unique to EBV and closely related γ1-herpesviruses of Old World primates identified an early EBV lytic cycle gene, BNLF2a, which efficiently blocks antigen-specific CD8+ T cell recognition through HLA-A–, HLA-B–, and HLA-C–restricting alleles when expressed in target cells in vitro. The small (60–amino acid) BNLF2a protein mediated its effects through interacting with the TAP complex and inhibiting both its peptide- and ATP-binding functions. Furthermore, this targeting of the major histocompatibility complex class I pathway appears to be conserved among the BNLF2a homologues of Old World primate γ1-herpesviruses. Thus, even the acquisition of latent cycle genes endowing unique growth-transforming ability has not liberated these agents from evolutionary pressure to evade CD8+ T cell control over virus replicative foci.
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6 August 2007
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July 09 2007
A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates
Andrew D. Hislop,
Andrew D. Hislop
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
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Maaike E. Ressing,
Maaike E. Ressing
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
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Daphne van Leeuwen,
Daphne van Leeuwen
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
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Victoria A. Pudney,
Victoria A. Pudney
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
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Daniëlle Horst,
Daniëlle Horst
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
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Danijela Koppers-Lalic,
Danijela Koppers-Lalic
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
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Nathan P. Croft,
Nathan P. Croft
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
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Jacques J. Neefjes,
Jacques J. Neefjes
3Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
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Alan B. Rickinson,
Alan B. Rickinson
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
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Emmanuel J.H.J. Wiertz
Emmanuel J.H.J. Wiertz
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
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Andrew D. Hislop
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
Maaike E. Ressing
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
Daphne van Leeuwen
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
Victoria A. Pudney
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
Daniëlle Horst
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
Danijela Koppers-Lalic
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
Nathan P. Croft
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
Jacques J. Neefjes
3Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
Alan B. Rickinson
1Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK
Emmanuel J.H.J. Wiertz
2Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
CORRESPONDENCE Alan B. Rickinson: [email protected]
Abbreviations used: EBNA, EBV nuclear antigen; HA, hemagglutinin; IRES, internal ribosome entry site; LCL, lymphoblastoid cell line; LCV, lymphocryptovirus; MJS, MelJuSo; ORF, open reading frame; TAP, transporter associated with antigen processing.
A.D. Hislop and M.E. Ressing contributed equally to this work.
Received:
February 05 2007
Accepted:
June 01 2007
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (8): 1863–1873.
Article history
Received:
February 05 2007
Accepted:
June 01 2007
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Citation
Andrew D. Hislop, Maaike E. Ressing, Daphne van Leeuwen, Victoria A. Pudney, Daniëlle Horst, Danijela Koppers-Lalic, Nathan P. Croft, Jacques J. Neefjes, Alan B. Rickinson, Emmanuel J.H.J. Wiertz; A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates . J Exp Med 6 August 2007; 204 (8): 1863–1873. doi: https://doi.org/10.1084/jem.20070256
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