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Updated: Aug 9, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Hypoxic-response elements in the oncolytic parvovirus Minute virus of mice do not allow for increased vector
Charlotte Servais1, Perrine Caillet-Fauquet2, Marie-Louise Draps2
1Laboratoire de Cytologie et de Cancérologie Expérimentale, IBMM-IRIBHM, Université Libre de Bruxelles, 12 rue des Professeurs Jeener et Brachet, B-6041 Gosselies, Belgium.
Abstract:
Vectors derived from the autonomous parvovirus Minute virus of mice, MVM(p), are promising tools for the gene therapy of cancer. The validation of their in vivo anti-tumour effect is, however, hampered by the difficulty to produce high-titre stocks. In an attempt to increase vector titres, host cells were subjected to low oxygen tension (hypoxia). It has been shown that a number of viruses are produced at higher titres under these conditions. This is the case, among others, for another member of the family Parvoviridae, the erythrovirus B19 virus. Hypoxia stabilizes a hypoxia-inducible transcription factor (HIF-1alpha) that interacts with a 'hypoxia-responsive element' (HRE), the consensus sequence of which ((A)/(G)CGTG) is present in the B19 and MVM promoters. Whilst the native P4 promoter was induced weakly in hypoxia, vector production was reduced dramatically, and adding HRE elements to the P4 promoter of the vector did not alleviate this reduction. Hypoxia has many effects on cell metabolism. Therefore, even if the P4 promoter is activated, the cellular factors that are required for the completion of the parvoviral life cycle may not be expressed.
Insights
Investigating hypoxia for Minute virus of mice (MVM) gene therapy vectors revealed that low oxygen tension significantly reduced vector production, despite potential promoter activation. This suggests metabolic changes hinder parvovirus replication under hypoxic conditions.
Area of Science:
- Molecular Virology
- Gene Therapy
- Cancer Research
Background:
- Autonomous parvoviruses like Minute virus of mice (MVM) are explored for cancer gene therapy.
- High-titer MVM vector production is challenging for in vivo studies.
- Hypoxia (low oxygen) can enhance viral production for some viruses, including erythrovirus B19.
Purpose of the Study:
- To investigate if hypoxia can increase MVM vector titers.
- To explore the role of hypoxia-inducible transcription factors (HIF-1alpha) and hypoxia-responsive elements (HREs) in MVM vector production.
Main Methods:
- Subjecting host cells to low oxygen tension (hypoxia).
- Analyzing MVM P4 promoter activity under hypoxia.
- Assessing MVM vector production yields in hypoxic conditions.
- Introducing HRE elements into the MVM P4 promoter.
Main Results:
- Hypoxia weakly induced the native MVM P4 promoter.
- MVM vector production was dramatically reduced under hypoxic conditions.
- Adding HRE elements did not improve vector production in hypoxia.
Conclusions:
- Hypoxia does not enhance MVM vector production and significantly reduces it.
- Cellular metabolic changes induced by hypoxia may impede parvoviral life cycle completion, overriding promoter activation.
