Frontiers in Microbiology (Mar 2023)

Regulated control of virus replication by 4-hydroxytamoxifen-induced splicing

  • Zhenghao Zhao,
  • Busen Wang,
  • Shipo Wu,
  • Zhe Zhang,
  • Yi Chen,
  • Jinlong Zhang,
  • Yudong Wang,
  • Danni Zhu,
  • Danni Zhu,
  • Yao Li,
  • Jinghan Xu,
  • Lihua Hou,
  • Wei Chen

DOI
https://doi.org/10.3389/fmicb.2023.1112580
Journal volume & issue
Vol. 14

Abstract

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Designing a modified virus that can be controlled to replicate will facilitate the study of pathogenic mechanisms of virus and virus–host interactions. Here, we report a universal switch element that enables precise control of virus replication after exposure to a small molecule. Inteins mediate a traceless protein splicing–ligation process, and we generate a series of modified vesicular stomatitis virus (VSV) with intein insertion into the nucleocapsid, phosphoprotein, or large RNA-dependent RNA polymerase of VSV. Two recombinant VSV, LC599 and LY1744, were screened for intein insertion in the large RNA-dependent RNA polymerase of VSV, and their replication was regulated in a dose-dependent manner with the small molecule 4-hydroxytamoxifen, which induces intein splicing to restore the VSV replication. Furthermore, in the presence of 4-hydroxytamoxifen, the intein-modified VSV LC599 replicated efficiently in an animal model like a prototype of VSV. Thus, we present a simple and highly adaptable tool for regulating virus replication.

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