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Title: Efficient transduction of cytotoxic and anti-HIV-1 genes by a gene-regulatable lentiviral vector.
Authors: Shinoda, Yasuhiko
Hieda, Kuniko
Koyanagi, Yoshio  kyouindb  KAKEN_id
Suzuki, Youichi
Author's alias: 鈴木, 陽一
Keywords: Lentiviral vector
Mifepristone-regulatable system
Issue Date: Oct-2009
Publisher: Springer Verlag
Journal title: Virus genes
Volume: 39
Issue: 2
Start page: 165
End page: 175
Abstract: Lentiviral vectors modified from human immunodeficiency virus type 1 (HIV-1) offer a promising approach for gene therapy, facilitating transduction of genes into non-dividing cells both in vitro and in vivo. When transducing cytotoxic or anti-HIV genes, however, the vector must avoid self-inhibition by the transgene that can lead to a disruption in production of infectious virions. In this study, we constructed two HIV-1-based lentiviral vectors harboring the mifepristone-inducible gene expression unit in either the forward or the reverse orientation with respect to the direction of viral genomic RNA. The ability of these vectors to transduce cytotoxic and anti-HIV genes was evaluated. When human CD14 was used as a transgene, infectious lentiviral vectors were produced by both forward and reverse vector systems. CD14 expression was efficiently induced in cells transduced by both lentiviral vectors following treatment with mifepristone. However, a higher level of basal transgene expression was observed in the forward vector system in the absence of mifepristone. In contrast, high titers of infectious lentiviral vector containing the cytotoxic vesicular stomatitis virus M gene were successfully generated using the reverse vector, but not the forward vector. In addition, when a VPS4B-dominant negative mutant against HIV-1 budding was cloned into the reverse vector, significant amounts of lentiviral vector were obtained. Subsequent transduction of cells with the VPS4B mutant resulted in approximately 50% inhibition of HIV-1 production only in the presence of mifepristone. Our study thus demonstrates that incorporation of a mifepristone-regulatable gene expression unit in the reverse orientation makes significant advances toward development of a lentiviral vector that allows transduction of harmful genes.
Rights: c 2009 Springer Science+Business Media, LLC.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
DOI(Published Version): 10.1007/s11262-009-0382-x
PubMed ID: 19554442
Appears in Collections:Journal Articles

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