Partial Deletion of Glycoprotein B5R Enhances Vaccinia Virus Neutralization Escape while Preserving Oncolytic Function
Partial Deletion of Glycoprotein B5R Enhances Vaccinia Virus Neutralization Escape while Preserving Oncolytic Function
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DOI：
10.1016/j.omto.2019.05.003
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发表时间：
2019-09-27
影响因子：
5.7
通讯作者：
Nakamura, Takafumi
中科院分区：
文献类型：
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作者：
Nakatake, Motomu;Kurosaki, Hajime;Nakamura, Takafumi
痘苗病毒（VV）已被用于溶瘤病毒疗法，但它存在宿主抗病毒免疫反应的风险。 VV 具有细胞外包膜病毒 (EEV) 形式，由覆盖有宿主衍生外膜的正常病毒颗粒组成，使其能够通过循环传播，同时逃避宿主免疫机制。然而，由于表面蛋白 B5R 的表达，EEV 的免疫抵抗只是部分的，该蛋白具有四个宿主免疫因子靶向的短共有重复 (SCR) 结构域。为了设计一种更有效的溶瘤病毒治疗病毒，我们通过去除减毒株 LC16mO 中的 SCR，开发了一种增强型免疫逃避溶瘤 VV。虽然仅删除 SCR 保留了病毒复制、后代产生和溶瘤活性，但删除整个 B5R 会导致病毒减毒。重要的是，与 B5R 野生型 EEV 相比，SCR 缺失 EEV 对 VV 免疫动物血清具有更高的中和抗性；此外，它保留了溶瘤功能，从而延长了用抗VV抗体治疗的荷瘤小鼠的存活时间。这些结果表明，部分SCR缺失增加了中和逃逸，而不影响VV的溶瘤效力，使其可用于在抗病毒抗体存在下治疗肿瘤。
Vaccinia virus (VV) has been utilized in oncolytic virotherapy, but it risks a host antiviral immune response. VV has an extracellular enveloped virus (EEV) form consisting of a normal virion covered with a host-derived outer membrane that enables its spread via circulation while evading host immune mechanisms. However, the immune resistance of EEV is only partial, owing to expression of the surface protein B5R, which has four short consensus repeat (SCR) domains that are targeted by host immune factors. To engineer a more effective virus for oncolytic virotherapy, we developed an enhanced immune-evading oncolytic VV by removing the SCRs from the attenuated strain LC16mO. Although deletion of only the SCRs preserved viral replication, progeny production, and oncolytic activity, deletion of whole B5R led to attenuation of the virus. Importantly, SCR-deleted EEV had higher neutralization resistance than did B5R-wild-type EEV against VV-immunized animal serum; moreover, it retained oncolytic function, thereby prolonging the survival of tumor-bearing mice treated with anti-VV antibody. These results demonstrate that partial SCR deletion increases neutralization escape without affecting the oncolytic potency of VV, making it useful for the treatment of tumors under the anti-virus antibody existence.