Development of an oncolytic herpes simplex virus using a tumor-specific HIF-responsive promoter

作者：Longo S L; Griffith C; Glass A; Shillitoe E J; Post D E^*

来源：Cancer Gene Therapy, 2011, 18(2): 123-134.

DOI：10.1038/cgt.2010.62

• hypoxia
• hypoxia-inducible factor (HIF)
• herpes simplex virus
• HSV
• oncolytic
• ICP4

We exploited the differential activation of hypoxia-inducible factor (HIF)-dependent gene expression in tumors versus normal tissue for the design of a targeted oncolytic herpes simplex virus type-1 (HSV-1). A gene that is essential for viral replication, infected cell polypeptide 4 (ICP4), was placed under the regulation of an HIF-responsive promoter and then introduced into the thymidine kinase locus (U(L)23) of HSV d120, which contains partial deletions in the two endogenous ICP4 genes. Recombinant HIF-HSV was isolated and their derivation from d120 was verified by expression of a truncated, non-functional form of ICP4 protein. Disruption of the U(L)23 locus was confirmed by loss of thymidine kinase expression and resistance to acyclovir. Unexpectedly, HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia. The lack of HIF-dependent ICP4 transgene expression by HIF-HSV was due to two factors that have not previously been reported-reversion of the ICP4 gene region to its wild-type configuration and increased HIF-transcriptional activity under normoxia when cells were infected with any strain of HSV-1. The findings that an oncolytic HSV-1 is genetically unstable and can activate a tumor-related promoter in a non-specific manner have important implications for any proposed use of this virus in cancer therapy. Cancer Gene Therapy (2011) 18, 123-134; doi: 10.1038/cgt.2010.62; published online 8 October 2010

• 出版日期2011-2