An oncolytic mutant of herpes simplex virus type-1 in which replication is governed by a promoter/enhancer of human papillomavirus type-16.
Although herpes simplex virus type-1 (HSV-1) can be used as an oncolytic virus it has the undesirable side effect of neurotoxicity. To create a virus with improved specificity for oral cancer we used a fragment of human papillomavirus type-16, which is frequently found in oral and cervical cancers, but not elsewhere. The upstream regulatory region, URR16, was shown to have a high level of transcriptional activity in three of four oral cancer cell lines but low activity in three cell lines derived from brain cancers. URR16 was therefore placed in HSV-1, replacing the promoter of the essential gene ICP4, and the resulting virus was named HSPV-1. When cells were infected with HSPV-1, ICP4 was expressed at levels that were not associated with the level of activity of URR16. The virus replicated in each type of cell to a final titer that showed a correlation with the level of expression of ICP4, but with no correlation to either the tumor of origin or the presence of HPV sequences in the cells. To find if some function of HSV-1 was affecting the activity of URR16, oral cancer cells were transfected with a URR-reporter construct and were then infected with virus. This induced transcription, which was attributed to immediate-early viral genes other than ICP4. A promoter/enhancer from a papillomavirus therefore has the potential to regulate the functions of an oncolytic strain of HSV-1, and is affected by functions of both the host cell and of HSV-1 itself.
Griffith
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C
Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Noonan
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S
Lou
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Shillitoe
E J
EJ
D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D009062:Mouth Neoplasms / Q000628:therapy / Q000821:virology; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D050504:Oncolytic Viruses / Q000235:genetics* / Q000254:growth & development; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014779:Virus Replication / Q000235:genetics*
D017874:Immediate-Early Proteins; C048925:herpes simplex virus, type 1 protein ICP4