Transoriptional Tayiting of herpes simplex virus for cell-specific replication

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We have developed a strategy for viral-mediated tumor therapy, where herpes simplex virus (HSV) replication and associated cytotoxicity are limited to a specific cell-type by the regulated expression of an essential immediate-early gene. A HSV vector, G92A,was constructed whose growth is restricted to albumin-expressing, dividing cells. G92A contains an albumin enhancer/promoter-ICP4 transgene within the thymidine kinase (tk) gene of the HSV-1 ICP4 deletion mutant d120. In addition, it contains the E.coli LacZ gene upstream of the ICP4 transgene, under control of the tk promoter. Therefore, G92A plaques stain bule with X-gal (lacZ+) in the presence of gancilovir (tk-). In Vitro, G92A replicates well in 3 human hepatoma (albumin-expressing) cell lines, destroying them, and not in 8 non-albumin-expressing human tumor cell lines. This cell-specificity was conserved in vivo, where the growth of established subcutaeous hepatoma tumors was significantly inhibited by a single inoculation of G92A,whereas, there was no effect on the growth of non-albumin expressing tumors. Mice inoculated intrahepatically with G92A,at doese that were 100% lethal with wild-type HSV,exhibited no symptoms of disease. These studies demonstrate the feasibility of confining a productive, lytic infection to defined cell types. HSV vectors containing other cell-specific regulatory regions should confer targeting to a variety of tumor types.