Selective inhibition of human T-lymphotropic virus type I-transformed human T-cell growth by a tax-targeted conditionally cytotoxic recombinant retrovirus.
Adult T-cell leukemia (ATL), a disorder associated with high mortality rates, arises from human T-lymphotropic virus type I (HTLV-I)-infected CD4+ T cells. We designed a retroviral vector-based gene therapy approach to ATL. The long terminal repeat (LTR) of HTLV-I is transactivated by the viral tax protein. We constructed a hybrid gene consisting of herpes simplex virus thymidine kinase (HSV TK) under the control of the HTLV-I LTR and inserted it into a retroviral vector. When HTLV-I-transformed and tax-expressing human T-cell lines were infected with this recombinant retrovirus (LNLTK alpha virus), they expressed high levels of HSV TK and exhibited increased sensitivity to acyclovir, a nucleoside analog that is converted to the toxic anabolite after phosphorylation by the HSV TK. On the other hand, the retroviral infection had little effect on acyclovir-induced cytotoxicity in HTLV-I-negative human hematopoietic cell lines. Our data may provide the prospect of the gene therapy for ATL by tax-targeted selective elimination of leukemic cells.
Fujita
M
M
Department of Oncology, Nagasaki University School of Medicine, Japan.
Murata
K
K
Shiku
H
H
D000212:Acyclovir / Q000494:pharmacology; D015139:Blotting, Southern; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism* / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D004274:DNA, Recombinant; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics* / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D015458:Leukemia, T-Cell / Q000628:therapy; D012091:Repetitive Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics
D004274:DNA, Recombinant; D016356:Gene Products, tax; D013937:Thymidine Kinase; D000212:Acyclovir