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首页> 外文期刊>Gene therapy >Engineering a serum-resistant and thermostable vesicular stomatitis virus G glycoprotein for pseudotyping retroviral and lentiviral vectors
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Engineering a serum-resistant and thermostable vesicular stomatitis virus G glycoprotein for pseudotyping retroviral and lentiviral vectors

机译：工程化抗血清和热稳定的水泡性口腔炎病毒G糖蛋白以假型化逆转录病毒和慢病毒载体

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摘要

Vesicular stomatitis virus G glycoprotein (VSV-G) is the most widely used envelope protein for retroviral and lentiviral vector pseudotyping; however, serum inactivation of VSV-G pseudotyped vectors is a significant challenge for in vivo gene delivery. To address this problem, we conducted directed evolution of VSV-G to increase its resistance to human serum neutralization. After six selection cycles, numerous common mutations were present. On the basis of their location within VSV-G, we analyzed whether substitutions in several surface exposed residues could endow viral vectors with higher resistance to serum. S162T, T230N and T368A mutations enhanced serum resistance, and additionally K66T, T368A and E380K substitutions increased the thermostability of VSV-G pseudotyped retroviral vectors, an advantageous byproduct of the selection strategy. Analysis of a number of combined mutants revealed that VSV-G harboring T230N+T368A or K66T+S162T+T230N+T368A mutations exhibited both higher in vitro resistance to human serum and higher thermostability, as well as enhanced resistance to rabbit and mouse serum. Finally, lentiviral vectors pseudotyped with these variants were more resistant to human serum in a murine model. These serum-resistant and thermostable VSV-G variants may aid the application of retroviral and lentiviral vectors to gene therapy.
机译：水泡性口腔炎病毒G糖蛋白（VSV-G）是逆转录病毒和慢病毒载体假型使用最广泛的包膜蛋白;然而，VSV-G假型载体的血清失活是体内基因递送的重大挑战。为了解决这个问题，我们进行了定向进化的VSV-G，以增加其对人血清中和的抵抗力。在六个选择周期后，出现了许多常见的突变。基于它们在VSV-G中的位置，我们分析了在多个表面暴露残基中的取代是否可以赋予病毒载体以更高的血清抗性。 S162T，T230N和T368A突变增强了血清抵抗力，此外，K66T，T368A和E380K替代增加了VSV-G伪型逆转录病毒载体的热稳定性，这是选择策略的有利副产品。对许多组合突变体的分析表明，带有T230N + T368A或K66T + S162T + T230N + T368A突变的VSV-G表现出更高的体外抗人血清抗性和更高的热稳定性，以及增强的抗兔和小鼠血清抗性。最后，用这些变体假型化的慢病毒载体在鼠模型中对人血清更具抗性。这些抗血清和热稳定的VSV-G变体可能有助于将逆转录病毒和慢病毒载体应用于基因治疗。

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