In vivo retrovirus-mediated herpes simplex virus thymidine kinase gene therapy approach for adult T cell leukemia in a rat model.
We have previously demonstrated that human T-lymphotropic virus type I (HTLV-I) tax-expressing human T cell lines are selectively eliminated in the presence of aciclovir, using a retroviral vector carrying the herpes simplex virus thymidine kinase (HSV TK) gene under the control of the long terminal repeat (LTR) of HTLV-I. Based on these findings in vitro, we investigated whether this system could also be effective in vivo, using a rat model. Following infection of the HTLV-I-transformed and tax-expressing rat T cell line TARS-1 with this retrovirus (LNLTK virus), high levels of HSV TK expression were observed and resulted in increased susceptibility to ganciclovir (GCV). Tumors were generated by subcutaneous injection of TARS-1 in newborn syngeneic WKA/H rats. While the tumors derived from infected TARS-1 cells with control virus, as well as uninfected cells, continued to grow in all the rats with or without administration of GCV, those derived from LNLTK-infected cells exhibited dramatic regression upon GCV treatment. These results indicate that the HTLV-I LTR-HSV TK system also causes selective elimination of HTLV-I-transformed, tax-expressing T cells in vivo. Therefore, our present study may provide a rationale for clinical gene therapy against adult T cell leukemia.
Murata
K
K
Department of Hematology, Nagasaki University School of Medicine.
Fujita
M
M
Yamada
Y
Y
Higami
Y
Y
Shimokawa
I
I
Tsukasaki
K
K
Tanaka
Y
Y
Maeda
M
M
Furukawa
K
K
Yoshiki
T
T
Shiku
H
H
Tomonaga
M
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics; D015316:Genetic Therapy; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D015458:Leukemia, T-Cell / Q000628:therapy*; D009368:Neoplasm Transplantation; D051381:Rats; D011919:Rats, Inbred Strains; D012091:Repetitive Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*
D000998:Antiviral Agents; D016356:Gene Products, tax; D013937:Thymidine Kinase; D015774:Ganciclovir