van Rikxoort, Marijke and Michaelis, Martin and Wolschek, Markus and Muster, Thomas and Egorov, Andrej and Seipelt, Joachim and Doerr, Hans Wilhelm and Cinatl, Jindrich (2012) Oncolytic Effects of a Novel Influenza A Virus Expressing Interleukin-15 from the NS Reading Frame. PLoS ONE, 7 (5). e36506. ISSN 1932-6203. (The full text of this publication is not available from this repository)
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Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences|
|Depositing User:||Martin Michaelis|
|Date Deposited:||24 Oct 2012 15:47|
|Last Modified:||19 Mar 2013 13:35|
|Resource URI:||https://kar.kent.ac.uk/id/eprint/31968 (The current URI for this page, for reference purposes)|