Hislop Andrew D, Ressing Maaike E, van Leeuwen Daphne, Pudney Victoria A, Horst Daniëlle, Koppers-Lalic Danijela, Croft Nathan P, Neefjes Jacques J, Rickinson Alan B, Wiertz Emmanuel J H J
Cancer Research UK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, UK.
J Exp Med. 2007 Aug 6;204(8):1863-73. doi: 10.1084/jem.20070256. Epub 2007 Jul 9.
gamma 1-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 alpha- and beta-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 gamma 1-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 gamma 1-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.
γ1疱疹病毒，如爱泼斯坦-巴尔病毒（EBV），具有通过潜伏性生长转化感染在体内扩增病毒载量的独特能力。它们是否像α和β疱疹病毒一样，被驱使积极逃避对复制性（裂解性）感染的免疫检测，仍是一个有争议的问题。最近的研究工作（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）促使我们重新审视这个问题，这些研究表明，随着EBV感染的细胞经历裂解周期，它们对EBV特异性CD8(+) T细胞识别的敏感性急剧下降，同时与抗原加工相关转运体（TAP）功能和表面人类组织相容性白细胞抗原（HLA）I类表达的降低相伴。对EBV以及旧世界灵长类动物密切相关的γ1疱疹病毒特有的基因进行筛选，鉴定出一个早期EBV裂解周期基因BNLF2a，当它在体外靶细胞中表达时，能通过HLA - A、HLA - B和HLA - C限制性等位基因有效阻断抗原特异性CD8(+) T细胞识别。小的（60个氨基酸）BNLF2a蛋白通过与TAP复合物相互作用并抑制其肽结合和ATP结合功能来介导其作用。此外，这种对主要组织相容性复合体I类途径的靶向作用在旧世界灵长类动物γ1疱疹病毒的BNLF2a同源物中似乎是保守的。因此，即使获得赋予独特生长转化能力的潜伏周期基因，这些病毒也未能从逃避CD8(+) T细胞对病毒复制灶控制的进化压力中解脱出来。
