Monday, February 25, 2013

Fighting Fire with Fire

To some it may seem counterintuitive to use an infection to cure a disease. Surprisingly enough, this is exactly what researchers have been doing using oncolytic virus therapy.  Oncolytic viruses are naturally occurring or engineered viruses that selectively target cancer cells by identifying common cancer characteristics such as defective immune responses or abnormalities in cellular signaling pathways. Once viruses infect the cancer cells, they replicate within the cell and eventually kill it.  As such, the infectious qualities of oncolytic viruses are becoming increasingly useful tools during cancer treatment. 

Past studies have shown great potential for oncolytic therapy using vesicular stomatitis virus, (VSV) -- a negative-strand RNA virus that generally infects insects, cattle, horses and pigs (1).  VSV has proven to be particularly conducive to oncolytic virus therapy as a result of its small easily manipulated genome and relative innocuity in humans (2). So far, VSV vectors have been used for immunization against HIV and influenza (2,3).  Additionally, testing has occurred that suggests that there is also potential of VSV as a recombinant cancer vaccine vector (4). 

Despite the high hopes for the use of VSV as oncolytic cancer treatment, a recent 2012 study suggests that human pancreatic ductal adenocarcinoma (PDA) cells do not consistently permit VSV infection (5).  In some cases, PDA cells retained all resistance and were still able to activate functional interferon (IFN) responses. As a result, the study of the interferons – proteins released by host cells to interrupt viral replication – and their association with oncolytic VSV infection is of great interest to researchers.

Earlier this year, a study published in Virology attempted to shed light on just how IFN pathways manage to inhibit VSV infection.  To test this hypothesis, a series of human PDA cell lines – all known to have genes associated with type I IFN pathways - were exposed to wild-type VSV and two VSV recombinants, in addition to a recombinant Sendai virus, recombinant respiratory syncytial virus and two recombinant adenoviruses.  The authors found that all cell lines sensed infection by VSV and there was little variability of IFN-α and β expression.  However, a few cell lines were resistant to the VSV recombinants.  These cells had considerably more expression variability of the IFN-stimulated antiviral genes MxA and OAS.   As a result, it has been proposed that MxA and OAS – after being triggered by type I IFN - are potential biomarkers for PDA resistance to VSV.  Additionally, it suggests that other oncolytic viruses could be similarly inhibited by type I IFN responses.

In the future, it would be beneficial to better understand the upregulation of Mxa and OAS in preventing the infection of VSV.  Additionally, the effects of infecting with multiple types of oncolytic viruses or using oncolytic therapy in conjunction with chemotherapy might serve to be effective cancer treatments.  While this study does show that there is some resistance to VSV in the treatment of human pancreatic ductal adenocarcinoma, it has still proven to be a promising treatment possibility. As such, one should not entirely rule out the use of VSV in oncolytic virus therapy.

Primary Article:

Moerdyk-Schauwecker M,  Shah NR, Murphy AM, Hastie E, Mukherjee P,  Grdzelishvili VZ (2013) Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: Role of type I interferon signaling. Virology 436: 221-234.  

Supporting Articles:

1.      Hastie E, Grdzelishvili VZ. (2012) Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer. J Gen Virol. 93:2529-45.

2.      Lichty BD, Power AT, Stojdl DF, Bell JC. (2004)Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med.  10: 210–216.

3.      Rose NF, Marx PA, Luckay A, Nixon DF, Moretto WJ, Donahoe SM, Montefiori D, Roberts A, Buonocore L, Rose JK (2001) An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants. Cell 106:539-546.

4.     Bridle BW, Boudreau JE,  Lichty BD,  Brunellière J,  Stephenson K, Koshy S, Bramson JL, and Wan Y.(2009)Vesicular stomatitis virus as a novel cancer vaccine vector to prime antitumor immunity amenable to rapid boosting with adenovirus. Mol Ther. 17:1814-1821

5.      Murphy AM, Besmer DM, Moerdyk-Schauwecker M, Moestl N, Ornelles DA, Mukherjee P, Grdzelishvili VZ. (2012)Vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma. J Virol. 86:3073-87.

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