Characterization of Oncolytic Herpesviruses

Abstract

<p> Oncolytic viruses are able to selectively replicate in tumour cells and are an attractive new avenue of cancer therapy that lacks the toxic side effects of current treatment modalities. HSV-1 mutants lacking ICPO are promising oncolytic vectors, however, the mechanisms behind viral oncolysis remain unclear. Since PML contributes to the repression of HSV-1 and also is downregulated in various types of cancer, but particularly in prostate cancer, PML has been implicated as a factor influencing the permissiveness of tumour cells to I CPO-null HSV-1 oncolysis. By screening a series of immortalized patient matched normal and tumour prostate epithelial cells for sensitivity to ICPO-null HSV-1 oncolysis and evaluating the levels of PML in each cell line, we were unable to establish a link between PML status and permissiveness to ICPO-null HSV-1 oncolytic vectors. Also, since a large proportion of the population possesses pre-existing immunity to HSV -1, which may hinder systemic administration of HSV-1 vectors, we sought to determine if BHV-1 could be an alternative oncolytic herpesvirus. BHV-1 was cytotoxic to various human immortalized and transformed cell lines in vitro, but was generally more restricted from normal human cells, suggesting that BHV -1 may have potential as an oncolytic virus. However, the sensitivity of human cells to BHV -1 infection did not correlate with type I IFN signaling, as has been demonstrated for other oncolytic viruses. Furthermore, neutralizing antibodies against HSV-1 were unable to cross-react with BHV -1 in vitro suggesting that pre-existing immunity to HSV -1 in humans may not hinder BHV -1 infection. It is hoped that these results will contribute to the understanding of viral mediated oncolysis and also provide some evidence that BHV-1 may be a new alternative oncolytic herpesvirus, however, in vivo studies are necessary to evaluate the oncolytic efficacy of BHV -1. </p>