ArticleAIDS research and therapy2008
Stable gene transfer of CCR5 and CXCR4 siRNAs by sleeping beauty transposon system to confer HIV-1 resistance.
Article in AIDS research and therapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- Genetic Strategies for HIV Treatment and Prevention.Molecular therapy. Nucleic acids · 2018Review
- RNAi combining Sleeping Beauty transposon system inhibits ex vivo expression of foot-and-mouth disease virus VP1 in transgenic sheep cells.Scientific reports · 2017Article
- Engineering T Cells to Functionally Cure HIV-1 Infection.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Review
- RNAi-Mediated CCR5 Knockdown Provides HIV-1 Resistance to Memory T Cells in Humanized BLT Mice.Molecular therapy. Nucleic acids · 2015Article
- RNA interference approaches for treatment of HIV-1 infection.Genome medicine · 2015Article
- Progress toward curing HIV infection with hematopoietic cell transplantation.Stem cells and cloning : advances and applications · 2015Review
- C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection.Applied & translational genomics · 2013Review
- Zinc finger protein designed to target 2-long terminal repeat junctions interferes with human immunodeficiency virus integration.Human gene therapy · 2012Article
- Zinc-finger nuclease editing of human cxcr4 promotes HIV-1 CD4(+) T cell resistance and enrichment.Molecular therapy : the journal of the American Society of Gene Therapy · 2012Article
- Engineering HIV-1-resistant T-cells from short-hairpin RNA-expressing hematopoietic stem/progenitor cells in humanized BLT mice.PloS one · 2012Article
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Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThus far gene therapy strategies for HIV/AIDS have used either conventional retroviral vectors or lentiviral vectors for gene transfer. Although highly efficient, their use poses a certain degree of risk in terms of viral mediated oncogenesis. Sleeping Beauty (SB) transposon system offers a non-viral method of gene transfer to avoid this possible risk. With respect to conferring HIV resistance, stable knock down of HIV-1 coreceptors CCR5 and CXCR4 by the use of lentiviral vector delivered siRNAs has proved to be a promising strategy to protect cells from HIV-1 infection. In the current studies our aim is to evaluate the utility of SB system for stable gene transfer of CCR5 and CXCR4 siRNA genes to derive HIV resistant cells as a first step towards using this system for gene therapy.
resultsTwo well characterized siRNAs against the HIV-1 coreceptors CCR5 and CXCR4 were chosen based on their previous efficacy for the SB transposon gene delivery. The siRNA transgenes were incorporated individually into a modified SB transfer plasmid containing a FACS sortable red fluorescence protein (RFP) reporter and a drug selectable neomycin resistance gene. Gene transfer was achieved by co-delivery with a construct expressing a hyperactive transposase (HSB5) into the GHOST-R3/X4/R5 cell line, which expresses the major HIV receptor CD4 and and the co-receptors CCR5 and CXCR4. SB constructs expressing CCR5 or CXCR4 siRNAs were also transfected into MAGI-CCR5 or MAGI-CXCR4 cell lines, respectively. Near complete downregulation of CCR5 and CXCR4 surface expression was observed in transfected cells. During viral challenge with X4-tropic (NL4.3) or R5-tropic (BaL) HIV-1 strains, the respective transposed cells showed marked viral resistance.
conclusionSB transposon system can be used to deliver siRNA genes for stable gene transfer. The siRNA genes against HIV-1 coreceptors CCR5 and CXCR4 are able to downregulate the respective cell surface proteins and thus confer resistance against viral infection by restricting viral entry. These studies have demonstrated for the first time the utility of the non-viral SB system in conferring stable resistance against HIV infection and paved the way for the use of this system for HIV gene therapy studies.
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Registered trials
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