Heterologous Human Immunodeficiency Virus Type 1 Lentiviral Vectors Packaging a Simian Immunodeficiency Virus-Derived Genome Display a Specific Postentry Transduction Defect in Dendritic Cells
Open Access
- 1 September 2003
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 77 (17) , 9295-9304
- https://doi.org/10.1128/jvi.77.17.9295-9304.2003
Abstract
Heterologous lentiviral vectors (LVs) represent a way to address safety concerns in the field of gene therapy by decreasing the possibility of genetic recombination between vector and packaging constructs and the generation of replication-competent viruses. Using described LVs based on human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus MAC251 (SIVMAC251), we asked whether heterologous virion particles in which trans-acting factors belonged to HIV-1 and cis elements belonged to SIVMAC251 (HIV-siv) would behave as parental homologous vectors in all cell types. To our surprise, we found that although the heterologous HIV-siv vector was as infectious as its homologous counterpart in most human cells, it was defective in the transduction of dendritic cells (DCs) and, to a lesser extent, macrophages. In DCs, the main postentry defect was observed in the formation of two-long-terminal-repeat circles, despite the fact that full-length proviral DNA was being synthesized and was associated with the nucleus. Taken together, our data suggest that heterologous HIV-siv vectors display a cell-dependent infectivity defect, most probably at a post-nuclear entry migration step. As homologous HIV and SIV vectors do transduce DCs, we believe that these results underscore the importance of a conserved interaction between cis elements and trans-acting viral factors that is lost or suboptimal in heterologous vectors and essential only in the transduction of certain cell types. For gene therapy purposes, these findings indicate that the cellular tropism of LVs can be modulated not only through the use of distinct envelope proteins or tissue-specific promoters but also through the specific combinatorial use of packaging and transfer vector constructs.Keywords
This publication has 81 references indexed in Scilit:
- Reassessment of the Roles of Integrase and the Central DNA Flap in Human Immunodeficiency Virus Type 1 Nuclear ImportJournal of Virology, 2002
- Wild-Type Levels of Nuclear Localization and Human Immunodeficiency Virus Type 1 Replication in the Absence of the Central DNA FlapJournal of Virology, 2002
- Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivoBlood, 2002
- High Levels of Transduction of Human Dendritic Cells with Optimized SIV VectorsMolecular Therapy, 2002
- Cytoplasmic Recruitment of INI1 and PML on Incoming HIV Preintegration ComplexesMolecular Cell, 2001
- Use of Helper-Free Replication-Defective Simian Immunodeficiency Virus-Based Vectors To Study Macrophage and T Tropism: Evidence for Distinct Levels of Restriction in Primary Macrophages and a T-Cell LineJournal of Virology, 2001
- Rev-Independent Expression of Syntheticgag-polGenes of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus: Implications for the Safety of Lentiviral VectorsHuman Gene Therapy, 2000
- Transduction of human macrophages using a stable HIV-1/HIV-2-derived gene delivery systemGene Therapy, 1998
- In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral VectorScience, 1996
- Effect of Fv-1 gene product on synthesis of N-tropic and B-tropic murine leukemia viral RNACell, 1976