Transcriptional retargeting of herpes simplex virus for cell-specific replication to control cancer

Abstract

Introduction

Oncolytic virotherapy has emerged as a novel frontier in the treatment of cancer. Among the viruses that entered clinical trials are the oncolytic herpes simplex virus-1 (HSV-1). Current oncolytic HSV-1 approved for clinical practice, and those in clinical trials are attenuated viruses, often deleted in the neurovirulence gene γ₁34.5, and in additional genes, which may result in a much more attenuated virus with reduced replication efficiency. Therefore, the transcriptional retargeting strategy by modifying the regulator elements flanking essential viral genes to achieve tumor-specific replication while maintaining as much of the viral genome has been representing alternative promising oncolytic virotherapy modality.

Materials and methods

In this communication, we aimed to review extensive studies on transcriptional retargeting strategy with HSV-1 genome engineered on immediate–early ICP4 gene, late γ₁34.5 gene or early ICP6 gene as well as multiple-regulated oncolytic HSV1 through combining transcriptional retargeting and translational control. Design modality based on differential cellular background, advantage, and potential clinic limitation of the innovative oncolytic HSV-1 was described, and prospective and challenge of transcriptional retargeting strategy were collectively summarized.

Conclusion

Transcriptional retargeting strategy holds great promise in retaining tumor specificity as well as full replication capacity of oncolytic virus in the target cell as urgently required by clinical trials. Future efforts should be aimed toward the development of multiple-component targeted oncolytic virus such as combing the transcriptional retargeting strategy and genetically attenuated modulation or post-transcriptional control that will be the most effective at generating truly tumor selective vectors.

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