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GENE THERAPY

A Third-Generation Lentivirus Vector with a Conditional Packaging System

Tom Dull, Romain Zufferey, Michael Kelly, R. J. Mandel, Minh Nguyen, Didier Trono, Luigi Naldini
Tom Dull
Cell Genesys, Foster City, California, and
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Romain Zufferey
Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland
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Michael Kelly
Cell Genesys, Foster City, California, and
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R. J. Mandel
Cell Genesys, Foster City, California, and
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Minh Nguyen
Cell Genesys, Foster City, California, and
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Didier Trono
Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland
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Luigi Naldini
Cell Genesys, Foster City, California, and
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DOI: 10.1128/JVI.72.11.8463-8471.1998
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ABSTRACT

Vectors derived from human immunodeficiency virus (HIV) are highly efficient vehicles for in vivo gene delivery. However, their biosafety is of major concern. Here we exploit the complexity of the HIV genome to provide lentivirus vectors with novel biosafety features. In addition to the structural genes, HIV contains two regulatory genes, tat and rev, that are essential for HIV replication, and four accessory genes that encode critical virulence factors. We previously reported that the HIV type 1 accessory open reading frames are dispensable for efficient gene transduction by a lentivirus vector. We now demonstrate that the requirement for the tat gene can be offset by placing constitutive promoters upstream of the vector transcript. Vectors generated from constructs containing such a chimeric long terminal repeat (LTR) transduced neurons in vivo at very high efficiency, whether or not they were produced in the presence of Tat. When the rev gene was also deleted from the packaging construct, expression of gag and pol was strictly dependent on Rev complementation in trans. By the combined use of a separate nonoverlapping Rev expression plasmid and a 5′ LTR chimeric transfer construct, we achieved optimal yields of vector of high transducing efficiency (up to 107transducing units [TU]/ml and 104 TU/ng of p24). This third-generation lentivirus vector uses only a fractional set of HIV genes: gag, pol, and rev. Moreover, the HIV-derived constructs, and any recombinant between them, are contingent on upstream elements and trans complementation for expression and thus are nonfunctional outside of the vector producer cells. This split-genome, conditional packaging system is based on existing viral sequences and acts as a built-in device against the generation of productive recombinants. While the actual biosafety of the vector will ultimately be proven in vivo, the improved design presented here should facilitate testing of lentivirus vectors.

  • Copyright © 1998 American Society for Microbiology
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A Third-Generation Lentivirus Vector with a Conditional Packaging System
Tom Dull, Romain Zufferey, Michael Kelly, R. J. Mandel, Minh Nguyen, Didier Trono, Luigi Naldini
Journal of Virology Nov 1998, 72 (11) 8463-8471; DOI: 10.1128/JVI.72.11.8463-8471.1998

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A Third-Generation Lentivirus Vector with a Conditional Packaging System
Tom Dull, Romain Zufferey, Michael Kelly, R. J. Mandel, Minh Nguyen, Didier Trono, Luigi Naldini
Journal of Virology Nov 1998, 72 (11) 8463-8471; DOI: 10.1128/JVI.72.11.8463-8471.1998
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KEYWORDS

Genetic Vectors
HIV-1
lentivirus

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