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Mol Ther Methods Clin Dev. 2014 Feb 12;1:11. doi: 10.1038/mtm.2013.11. eCollection 2014.

Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.

Author information

1
Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
2
UCLA AIDS Institute , Los Angeles, California, USA ; Division of Hematology-Oncology, David Geffen School of Medicine at UCLA , Los Angeles, California, USA.
3
Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, Indiana, USA.
4
Institute of Experimental Hematology, Hannover Medical School , Hannover, Germany.
5
Calimmune Inc. , Los Angeles, California, USA.
6
UCLA AIDS Institute , Los Angeles, California, USA ; Division of Hematology-Oncology, David Geffen School of Medicine at UCLA , Los Angeles, California, USA ; UCLA School of Nursing , Los Angeles, California, USA.
7
UCLA AIDS Institute , Los Angeles, California, USA ; Department of Microbiology, Immunology, and Molecular Genetics, University of California , Los Angeles, California, USA ; Department of Medicine, University of California , Los Angeles, California, USA.

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.

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