Back to Search
Start Over
Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.
- Source :
-
Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2014 Feb 12; Vol. 1, pp. 11. Date of Electronic Publication: 2014 Feb 12 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4(+) T lymphocytes, and CD34(+) hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.
Details
- Language :
- English
- ISSN :
- 2329-0501
- Volume :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular therapy. Methods & clinical development
- Publication Type :
- Academic Journal
- Accession number :
- 26015947
- Full Text :
- https://doi.org/10.1038/mtm.2013.11