Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1981 Kraft Drive, Blacksburg, VA 24061, USA.
J Virol. 2010 Apr;84(8):3835-44. doi: 10.1128/JVI.01553-09. Epub 2010 Feb 10.
Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and intrinsically oncolytic because of its potent ability to induce apoptosis. Several studies have demonstrated that NDV is selectively cytotoxic to tumor cells but not normal cells due to defects in the interferon (IFN) antiviral responses of tumor cells. Many naturally occurring strains of NDV have an intact IFN-antagonistic function and can still replicate in normal human cells. To avoid potential toxicity issues with NDV, especially in cancer patients with immunosuppression, safe NDV-oncolytic vectors are needed. We compared the cell killing abilities of (i) a recombinant NDV (rNDV) strain, Beaudette C, containing an IFN-antagonistic, wild-type V protein (rBC), (ii) an isogenic recombinant virus with a mutant V protein (rBC-Edit virus) that induces increased IFN in infected cells and whose replication is restricted in normal human cells, and (iii) a recombinant LaSota virus with a virulent F protein cleavage site that is as interferon sensitive as rBC-Edit virus (LaSota V.F. virus). Our results indicated that the tumor-selective replication of rNDV is determined by the differential regulation of IFN-alpha and downstream antiviral genes induced by IFN-alpha, especially through the IRF-7 pathway. In a nude mouse model of human fibrosarcoma, we show that the IFN-sensitive NDV variants are as effective as IFN-resistant rBC virus in clearing the tumor burden. In addition, mice treated with rNDV exhibited no signs of toxicity to the viruses. These findings indicate that augmentation of innate immune responses by NDV results in selective oncolysis and offer a novel and safe virotherapy platform.
新城疫病毒（NDV）是一种禽副粘病毒，因其具有强烈诱导细胞凋亡的能力，因此对肿瘤具有选择性和内在的溶瘤作用。多项研究表明，由于肿瘤细胞干扰素（IFN）抗病毒反应的缺陷，NDV 对肿瘤细胞具有选择性细胞毒性，但对正常细胞没有毒性。许多天然存在的 NDV 株具有完整的 IFN 拮抗功能，仍能在正常的人类细胞中复制。为了避免 NDV 潜在的毒性问题，特别是在免疫抑制的癌症患者中，需要安全的 NDV 溶瘤载体。我们比较了以下三种病毒的细胞杀伤能力：（i）一种含有 IFN 拮抗野生型 V 蛋白的重组 NDV（rNDV）株（Beaudette C，rBC），（ii）一种具有突变 V 蛋白的同基因重组病毒（rBC-Edit 病毒），该病毒在感染细胞中诱导 IFN 增加，其复制在正常人类细胞中受到限制，以及（iii）一种具有毒力 F 蛋白切割位点的重组 LaSota 病毒，其对 IFN 的敏感性与 rBC-Edit 病毒相同（LaSota V.F. 病毒）。我们的结果表明，rNDV 的肿瘤选择性复制取决于 IFN-α诱导的 IFN-α和下游抗病毒基因的差异调节，特别是通过 IRF-7 途径。在人纤维肉瘤裸鼠模型中，我们表明，IFN 敏感的 NDV 变体与 IFN 抗性 rBC 病毒一样有效地清除肿瘤负担。此外，用 rNDV 治疗的小鼠对病毒没有表现出毒性迹象。这些发现表明，NDV 增强先天免疫反应可导致选择性溶瘤，并为新型安全的病毒治疗平台提供了依据。
