Hypoxic-response elements in the oncolytic parvovirus Minute virus of mice do not allow for increased vector production at low oxygen concentration.
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.
Servais
Charlotte
C
Laboratoire de Cytologie et de Cancérologie Expérimentale, IBMM-IRIBHM, Université Libre de Bruxelles, 12 rue des Professeurs Jeener et Brachet, B-6041 Gosselies, Belgium.
Caillet-Fauquet
Perrine
P
Laboratoire de Virologie Moléculaire, Faculté de Médecine, Campus Erasme, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Bruxelles, Belgium.
Draps
Marie-Louise
ML
Laboratoire de Virologie Moléculaire, Faculté de Médecine, Campus Erasme, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Bruxelles, Belgium.
Velu
Thierry
T
Laboratoire de Cytologie et de Cancérologie Expérimentale, IBMM-IRIBHM, Université Libre de Bruxelles, 12 rue des Professeurs Jeener et Brachet, B-6041 Gosselies, Belgium.
de Launoit
Yvan
Y
UMR 8117 CNRS, Université de Lille 1, Institut Pasteur Lille, Institut de Biologie de Lille, Lille, France.|Laboratoire de Virologie Moléculaire, Faculté de Médecine, Campus Erasme, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Bruxelles, Belgium.
Brandenburger
Annick
A
Laboratoire de Cytologie et de Cancérologie Expérimentale, IBMM-IRIBHM, Université Libre de Bruxelles, 12 rue des Professeurs Jeener et Brachet, B-6041 Gosselies, Belgium.
D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D005822:Genetic Vectors / Q000096:biosynthesis*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008915:Minute Virus of Mice / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003035:Cobalt; C018021:cobaltous chloride