HIV vector-mediated targeted suicide gene therapy for adult T-cell leukemia.
We investigated the potential efficacy of treating adult T-cell leukemia (ATL) using a gene therapeutic approach involving the use of a herpes simplex virus-thymidine kinase (HSV-TK)-mediated suicide system. Human immunodeficiency virus (HIV)-based vectors containing the HSV-TK gene were constructed to achieve targeted gene transfer into CD4-positive ATL cells, after which the transduced cells were selectively killed by treatment with ganciclovir (GCV). To examine the utility of HIV vectors in vivo, ATL-NOD-SCID mice were prepared by intraperitoneal injection of 1 x 10(7) MT2 cells into NK-depleted nonobese diabetic/severely compromised immunodeficient (NOD-SCID) mice. Thereafter, 1 ml of concentrated HIV vector expressing HSV-TK (HXCTKN) or GFP (HXGFP) stock was injected into the intraperitoneal cavity, and GCV was administered twice a day for 5 days. Fluorescence-activated cell sorting (FACS) analysis showed that 7-11% of MT2 or HUT102 cells recovered from the peritoneal cavity were transduced with the HXGFP. After 3 weeks, plasma sIL2-R alpha levels were significantly lower in mice administered HXCTKN than in those administered HXGFP. Moreover, HXCTKN-injected mice survived significantly longer than HXGFP-injected mice. Taken together, these findings suggest that HIV vectors could be used for in vivo targeted gene transfer into ATL cells and could thus serve as the basis for the development of effective new therapies for the treatment of ATL.
Miyake
K
K
Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan. kmiyake@nms.ac.jp
Inokuchi
K
K
Miyake
N
N
Dan
K
K
Shimada
T
T
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D015774:Ganciclovir / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006678:HIV / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000097:blood; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods
D000998:Antiviral Agents; D007376:Interleukin-2; D013937:Thymidine Kinase; D015774:Ganciclovir