Thursday, December 8, 2016

Reovirus: a cure for liver cancer?

Hepatocyte carcinoma is one of the most common cancer types on a global scale. It is responsible for approximately one million deaths each year making it a major cause of cancer related deaths. The development of Hepatocyte carcinoma is associated with chronic infections with Hepatitis C virus.  Owing to the development of an inflammatory environment in the liver, hepatitis C virus (HCV)-infected patients are at a high risk of developing Hepatocyte carcinoma (HCC). This connection creates a possibility to prevent Hepatocyte carcinoma through techniques used to neutralize Hepatitis C virus infections.
It has been known that a majority of Hepatocyte carcinoma development is associated with infections with related viruses such as HBV and HCV. Therefore, as mentioned above, techniques to prevent viral infections can be useful by reducing Hepatocyte carcinoma. A primary article, published earlier this year explores the use of mammalian orthoreovirus superinfection as a treatment for liver cancer through host cell immune response. Mammalian orthoreovirus (or reovirus) is a double stranded DNA virus with segmented genome. This virus is known to have very little pathogenic effects on human beings which makes it a good candidate for viral therapy. The authors of this primary article mentioned above take advantage of this property and use it as an agent against HCC development.
Having confirmed the ability of mammalian reovirus to infect HCC cells that metastasized, the authors infected normal liver cells samples containing both enriched hepatocytes and liver mononuclear cells (LMCs). In order to do so, the cells were fractionated into two groups containing each cell type present and reovirus was introduced to the fractionated samples. It was seen that the reovirus was able to infect the non cancerous cells without causing any cytopathic effect. Furthermore, the researchers observed expressions of cellular cytokine responses upon reovirus infection of both cancerous and non cancerous liver cells. This response against reovirus infection is key for the uses of reovirus in the prevention of HCV infection and the associated Hepatocyte carcinoma.
After learning the ability of reovirus to infect hepatocytes and LMCs, the authors went on to examine the anti-HCC functions of reovirus infection. Immunocompromised mice bearing xenografts of HUH7 and HUH7-JFH1 (HCV containing HUH7 cells) cells were used. Injections of reovirus to these tumors were able to significantly slow the growth of the tumor down. Reduced expression of HCV protein 5A was also found in these tumor cells suggesting a connection between the anti-HCC and anti-HCV effects of reovirus. In addition, the authors also found reovirus injection was associated with necrosis of the immunocompromised cells and caused the anti-HCC effects through toxicity of the cells. This caused severe reactions in the mice used and mandated early sacrifice. To avoid this, the researchers infected immunocompetent mice and infected them with UV-inactivated reoviruses and repeated the experiments. Results from these experiments showed reovirus infections still halted tumor growth. The fact that the cells were immunocompetent and the reovirus was inactivated rules out lytic anti-tumor action which, in turn, suggests that there is some sort of cell response to the infections with reovirus that inhibits tumor growth.

Figure 1: Tumor growth is hindered by single injection with reovirus.
The next step in this study was to understand this anti-tumor response of the cells. An increase in natural killer (NK) cells were observed when the tumors were injected with reovirus. This gave a hint on the response mechanism the cells used. Previous studies have shown that type 1 interferon induces these cell types as a response to foreign body infection. To confirm this is the case the authors injected the tumors with reovirus supplemented with type 1 interferon blocking antibody. This resulted in a significant decrease of NK cell count and, subsequently, tumor growth. It was also observed that this reovirus injection technique is ineffective in tumors of SCID cells that had compromised cellular response systems. Thus, reovirus induced anti-HCC immunity is dependent upon type 1 interferon, which in turn activates NK cells, enabling them to recognise and kill tumour targets. These anti-HCC and anti-HCV effects of reovirus infection were observed both in vivo and in vitro experiments.

Figure 2: Increase in NK cells (stained brown) is observed upon reovirus infection.
Then, the authors tried to see if the antiviral and anticancer effects of reovirus extended beyond HCV and associated Hepatocyte carcinoma. PLC/PRF/5 cells (HCC cells containing integrated HBV), and Daudi cells, which are derived from an Epstein–Barr virus (EBV)-positive Burkitt’s lymphoma, were infected with reovirus to see if infection resulted in antiviral responses which prevented the associated cancers. HBV surface antigen (HBsAg) was used to monitor HBV replication in cells. When PLC/PRF/5 cells were infected with reoviruses a significant decrease in HBsAg was observed. Moreover, reovirus infection of Daudi cells led to a significant reduction of EBV early antigen (EA)-positive cells. These results show the ability of reovirus as an antiviral and anticancer agent is not limited to HCV and HCC which was remarkable. This study also revealed that this broad antiviral effect was not seen when other typically oncolytic viruses such as HSV 1, Vaccinia virus and Edmonston strain of Measles virus which sets reoviruses apart and creates a great deal of interest in reovirus studies.

Samson, Adel, Matthew J. Bentham, Karen Scott, Gerard Nuovo, Abigail Bloy, Elizabeth Appleton, Robert A. Adair, Rajiv Dave, Adam Peckham-Cooper, Giles Toogood, Seishi Nagamori, Matthew Coffey, Richard Vile, Kevin Harrington, Peter Selby, Fiona Errington-Mais, Alan Melcher, and Stephen Griffin. "Oncolytic Reovirus as a Combined Antiviral and Anti-tumor Agent for the Treatment of Liver Cancer." Gut Online First(2016). Web.

Grassi et. al.. "Hepatitis C Virus Relies on Lipoproteins for Its Life Cycle." World Journal of Gastroenterology 22.6 (2016). Web.

Wirth et. al. "The Impact of the Revolution in Hepatitis C Treatment on Hepatocellular Carcinoma." Annals of Oncology : Official Journal of the European Society for Medical Oncology. U.S. National Library of Medicine, 18 May 2016. Web. 06 Dec. 2016.

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