Zika Virus with Increased CpG Dinucleotide Frequencies Shows Oncolytic Activity in Glioblastoma Stem Cells.

Ivan Trus,Nathalie Berube,Uladzimir Karniychuk,Volker Gerdts,Peng Jiang,Janusz Rak

doi:10.3390/v12050579

Abstract

We studied whether cytosine phosphate–guanine (CpG) recoding in a viral genome may provide oncolytic candidates with reduced infection kinetics in nonmalignant brain cells, but with high virulence in glioblastoma stem cells (GSCs). As a model, we used well-characterized CpG-recoded Zika virus vaccine candidates that previously showed genetic stability and safety in animal models. In vitro, one of the CpG-recoded Zika virus variants had reduced infection kinetics in nonmalignant brain cells but high infectivity and oncolytic activity in GSCs as represented by reduced cell proliferation. The recoded virus also efficiently replicated in GSC-derived tumors in ovo with a significant reduction of tumor growth. We also showed that some GSCs may be resistant to Zika virus oncolytic activity, emphasizing the need for personalized oncolytic therapy or a strategy to overcome resistance in GSCs. Collectively, we demonstrated the potential of the CpG recoding approach for oncolytic virus development that encourages further research towards a better understanding of host–tumor–CpG-recoded virus interactions.

Highlights

Cytosine–phosphate–guanine (CpG) dinucleotide frequencies are suppressed in vertebrate genomes and most RNA viruses [1,2]
It has been demonstrated that cellular Zinc-finger antiviral protein (ZAP) targets recoded viruses by binding to genomic regions enriched in CpG dinucleotides [3,4]
Efficacy of the CpG-recoded influenza virus vaccine has been demonstrated in mice; we showed full protection evoked by CpG-recoded Zika virus (ZIKV) vaccine candidates in mice challenged with lethal heterologous ZIKV [7]

Summary

Introduction

Cytosine–phosphate–guanine (CpG) dinucleotide frequencies are suppressed in vertebrate genomes and most RNA viruses [1,2]. The rational increase of CpG dinucleotide numbers in viral genomes has the potential to become a cutting-edge approach for vaccine development and an alternative to traditional live attenuated vaccines. The concept is to increase the number of CpG dinucleotides in an RNA viral genome while retaining the amino acid composition of encoded proteins that leads to impaired infection but robust protective host immune responses. It has been demonstrated that cellular Zinc-finger antiviral protein (ZAP) targets recoded viruses by binding to genomic regions enriched in CpG dinucleotides [3,4]. KHNYN inhibits replication of viruses containing an elevated number of CpG dinucleotides [5,6].

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Conclusion