Tumor-specific activity of cellular regulatory elements is down-regulated upon insertion into the herpes simplex virus genome.

Mandy Glass, Ariane Soling, Martin Messerle

Research output: Contribution to journalArticle

Abstract

Transcriptional targeting of viral genes is a promising strategy to achieve tumor-specific replication of oncolytic viruses. Due to its natural tropism, herpes simplex virus type 1 (HSV-1) may be an ideal tool for oncolytic therapy of brain tumors such as malignant glioblastoma. To study whether glioma-specific gene expression can be accomplished within the HSV-1 genome, four cellular regulatory elements were exemplarily studied. Whereas the human telomerase reverse transcriptase (hTERT) and survivin promoters and the nestin and vascular endothelial growth factor A (VEGF-A) enhancers displayed pronounced glioma specificity after plasmid transfection, only the nestin enhancer conferred a certain selectivity for glioma cells and notable activity when transferred into the viral genome. The nestin enhancer was also found to be highly useful for tumor cell-specific expression of a therapeutically relevant gene (interleukin-2) when tested in combination with the hTERT or simian virus 40 (SV40) early promoter in the HSV-1 genome. Because activity of the chosen promoter in a tumor is a prerequisite for the successful application of an oncolytic virus, we examined whether the activity of a promoter can be deduced from the amounts of cellular mRNA or protein expressed under its control. We found little correlation between promoter activity and mRNA levels of the corresponding gene, whereas protein expression was more closely related to promoter activity. We conclude that the cellular elements are differently regulated in the viral and cellular genomes. Mechanistic insight into the differential regulation is required to improve and refine the design of transcriptionally targeted HSV vectors.
Original languageEnglish
Pages (from-to)522-35
Number of pages14
JournalJournal of NeuroVirology
Volume14
DOIs
Publication statusPublished - Nov 2008
Externally publishedYes

Fingerprint

Nestin
Human Herpesvirus 1
Simplexvirus
Glioma
Oncolytic Viruses
Viral Genome
Genome
Neoplasms
Messenger RNA
Tropism
Simian virus 40
Viral Genes
Glioblastoma
Brain Neoplasms
Vascular Endothelial Growth Factor A
Interleukin-2
Transfection
Proteins
Plasmids
Gene Expression

Keywords

  • Oncolytic herpesvirus
  • Glioblastoma
  • Viral gene regulation
  • Transcriptional targeting

Cite this

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title = "Tumor-specific activity of cellular regulatory elements is down-regulated upon insertion into the herpes simplex virus genome.",
abstract = "Transcriptional targeting of viral genes is a promising strategy to achieve tumor-specific replication of oncolytic viruses. Due to its natural tropism, herpes simplex virus type 1 (HSV-1) may be an ideal tool for oncolytic therapy of brain tumors such as malignant glioblastoma. To study whether glioma-specific gene expression can be accomplished within the HSV-1 genome, four cellular regulatory elements were exemplarily studied. Whereas the human telomerase reverse transcriptase (hTERT) and survivin promoters and the nestin and vascular endothelial growth factor A (VEGF-A) enhancers displayed pronounced glioma specificity after plasmid transfection, only the nestin enhancer conferred a certain selectivity for glioma cells and notable activity when transferred into the viral genome. The nestin enhancer was also found to be highly useful for tumor cell-specific expression of a therapeutically relevant gene (interleukin-2) when tested in combination with the hTERT or simian virus 40 (SV40) early promoter in the HSV-1 genome. Because activity of the chosen promoter in a tumor is a prerequisite for the successful application of an oncolytic virus, we examined whether the activity of a promoter can be deduced from the amounts of cellular mRNA or protein expressed under its control. We found little correlation between promoter activity and mRNA levels of the corresponding gene, whereas protein expression was more closely related to promoter activity. We conclude that the cellular elements are differently regulated in the viral and cellular genomes. Mechanistic insight into the differential regulation is required to improve and refine the design of transcriptionally targeted HSV vectors.",
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Tumor-specific activity of cellular regulatory elements is down-regulated upon insertion into the herpes simplex virus genome. / Glass, Mandy; Soling, Ariane; Messerle, Martin.

In: Journal of NeuroVirology, Vol. 14, 11.2008, p. 522-35.

Research output: Contribution to journalArticle

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