Abstract
Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells. We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs). As hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma worldwide, we investigated the effect of ARV-PB1 against cells already infected with this virus. Both HCV replicon-containing and infected cells supported ARV-PB1 replication and underwent cytolysis. Finally, we generated in silico models to compare the structures of human reovirus- and ARV-PB1-derived S1 proteins, which are the primary targets of neutralizing antibodies. Tertiary alignments confirmed that ARV-PB1 differs from its human homolog, suggesting that immunity to human reoviruses would not be a barrier to its use. Therefore, ARV-PB1 can potentially expand the repertoire of oncolytic viruses for treatment of human hepatocellular carcinoma and other malignancies.
Highlights
Liver cancer is the third leading cause of cancer worldwide, and hepatocellular carcinoma (HCC)represents approximately 70%–80% of all cases [1]
We have isolated an avian orthoreovirus, Avian reoviruses (ARVs)-PB1, and demonstrated its cytolytic activity in vitro against several liver cancer cell lines, including those infected with hepatitis C virus (HCV)
Our results suggest the oncolytic potential of ARV-PB1
Summary
Liver cancer is the third leading cause of cancer worldwide, and hepatocellular carcinoma (HCC)represents approximately 70%–80% of all cases [1]. The incidence of HCC is expected to increase markedly in North America over the decades due to the high prevalence of hepatitis C virus (HCV). Despite studies into the pathogenesis of HCC, and attempts to enhance therapy, improvement in patient outcomes has been marginal. The use of oncolytic viruses (OVs) for therapy offers promise for cancers where survival outcomes are poor and treatment options are limited. The use of these viruses offers numerous advantages over conventional cancer therapies including reduced toxicity, treatments of relatively short duration, and the possibility of targeting micrometastases [3]. The oncolytic human herpes simplex virus 1 (HSV-1) carrying the granulocyte macrophage colony-stimulating factor (GM-CSF), known as T-VEC, was approved for melanoma treatment [10]
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