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Efficient Gene Delivery into Epstein–Barr Virus (EBV)-Transformed Human B Cells Mediated by Replication-Defective Herpes Simplex Virus-1 (HSV-1): A Gene Therapy Model for EBV-Related B Cell Malignancy

1998; Elsevier BV; Volume: 252; Issue: 3 Linguagem: Inglês

10.1006/bbrc.1998.9685

1090-2104

Toshiya Suzuki, Alain Piché, Keizo Kasono, Jialing Xiang, Jesús Gómez-Navarro, Shusuke Moriuchi, David Krisky, Thomas Oligino, Joseph C. Glorioso, Tyler J. Curiel, D T Curiel,

Cytomegalovirus and herpesvirus research

Subgroups of the B cell malignancies are known to be associated with Epstein–Barr virus (EBV) infection, especially in immunocompromised patients. These are fatal and refractory to conventional antineoplastic therapy. B cells are usually post-mitotic cells and even mitogen activated or transformed B cells have shown relative resistance against viral mediated gene transfer. To address this issue, we employed a replication-defective herpes simplex virus-1 (HSV-1) to mediate gene transfer into EBV-transformed B cells. The virus expresses the herpes simplex virus thymidine kinase (HSV-TK) and theE. coli lacZreporter genes and is designated T0Z.1. We used the lymphoblastoid cell line SWEIG as a model for human EBV-related B cell malignancy. This cell line was established byin vitroEBV infection of primary human peripheral blood mononuclear cells. When SWEIG cells were infected with T0Z.1, X-gal staining revealedlacZexpression in more than 20% cells even at multiplicity of infection (MOI) as low as 1 and the expression persisted for at least one week. Ganciclovir (GCV) administration after T0Z.1 infection effectively decreased the number of the infected tumor cells in a dose-responsive manner. Viral toxicity was analyzed by cell proliferation assay (MTS assay) and found to be little even at 10 MOI infection. Three MOI of the virus yielded maximum antineoplastic effect and more than 50% tumor cells were killed by HSV-TK/GCV. These results suggest the potential utility of replication-defective HSV-1 for the treatment of EBV-related B cell malignancies.