Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV.
Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV.
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EB病毒（EBV）相关的B细胞淋巴组织增生性疾病（LPD）造血干细胞或实体器官移植后仍然是一个威胁生命的并发症。病毒编码的基因产物EBER的表达已显示通过阻断PKR活化来防止细胞凋亡。由于PKR是针对单纯疱疹病毒的主要细胞防御，并且溶瘤HSV-1（oHSV）突变体在临床前模型中显示出有希望的抗肿瘤功效，因此我们试图确定EBV-LPD细胞是否易受oHSV感染。我们测试了三种来自神经母细胞瘤（NB）患者的原发性EBV感染的淋巴细胞培养物作为自然获得性EBV-LPD的模型。NB 12最感病，NB 122 R次之，NB 88 R2基本抗病。尽管EBER表达，PKR被oHSV感染激活。对oHSV的易感性与HSV受体nectin-1的表达相关。外源nectin-1表达逆转了NB 88 R2的抗性，而下调Nectin-1对NB 12的作用则减少了病毒进入。来源于EBV-LPD的异种移植物对oHSV注射仅表现出轻度（NB 12）或无（NB 88 R2）反应，而神经母细胞瘤细胞系表现出显著反应。我们得出结论，EBV-LPD对oHSV病毒治疗相对耐受，在某些情况下是由于病毒受体表达低，但也由于完整的抗病毒PKR信号传导。
Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. Because PKR is a major cellular defense against Herpes simplex virus, and oncolytic HSV-1 (oHSV) mutants have shown promising anti-tumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was most susceptible, NB122R was intermediate, and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas down-regulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a neuroblastoma cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases due to low virus receptor expression but also due to intact anti-viral PKR signaling.
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