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Journal of Virology, December 1998, p. 9873-9880, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery

Romain Zufferey,1 Thomas Dull,2 Ronald J. Mandel,2 Anatoly Bukovsky,2 Dulce Quiroz,2 Luigi Naldini,2 and Didier Trono1,*

Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland,1 and Cell Genesys, Foster City, California2

Received 1 June 1998/Accepted 13 August 1998

In vivo transduction of nondividing cells by human immunodeficiency virus type 1 (HIV-1)-based vectors results in transgene expression that is stable over several months. However, the use of HIV-1 vectors raises concerns about their safety. Here we describe a self-inactivating HIV-1 vector with a 400-nucleotide deletion in the 3' long terminal repeat (LTR). The deletion, which includes the TATA box, abolished the LTR promoter activity but did not affect vector titers or transgene expression in vitro. The self-inactivating vector transduced neurons in vivo as efficiently as a vector with full-length LTRs. The inactivation design achieved in this work improves significantly the biosafety of HIV-derived vectors, as it reduces the likelihood that replication-competent retroviruses will originate in the vector producer and target cells, and hampers recombination with wild-type HIV in an infected host. Moreover, it improves the potential performance of the vector by removing LTR sequences previously associated with transcriptional interference and suppression in vivo and by allowing the construction of more-stringent tissue-specific or regulatable vectors.

* Corresponding author. Mailing address: Department of Genetics and Microbiology, CMU, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Phone: (41 22) 702 5720. Fax: (41 22) 702 5721. E-mail: didier.trono{at}medecine.unige.ch.

Journal of Virology, December 1998, p. 9873-9880, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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