title: Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.
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.
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Orit
authors.initials: O
authors.lastname: Wolstein
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
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authors.initials: M
authors.lastname: Boyd
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Michelle
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authors.lastname: Millington
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Impey
authors.affiliation: UCLA AIDS Institute , Los Angeles, California, USA ; Division of Hematology-Oncology, David Geffen School of Medicine at UCLA , Los Angeles, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Boyer
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Annett
authors.initials: A
authors.lastname: Howe
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Frederic
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authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, Indiana, USA.
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authors.affiliation: Institute of Experimental Hematology, Hannover Medical School , Hannover, Germany.
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authors.affiliation: Institute of Experimental Hematology, Hannover Medical School , Hannover, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Nicolson
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Koldej
authors.affiliation: Calimmune Inc. , Los Angeles, California, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Calimmune Inc. , Los Angeles, California, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Keech
authors.affiliation: Calimmune Inc. , Los Angeles, California, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Camba Colón
authors.affiliation: Calimmune Inc. , Los Angeles, California, USA.
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authors.initials: L
authors.lastname: Breton
authors.affiliation: Calimmune Inc. , Los Angeles, California, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bartlett
authors.affiliation: 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.
authors.forename: Dong Sung
authors.initials: DS
authors.lastname: An
authors.affiliation: 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.
authors.forename: Irvin Sy
authors.initials: IS
authors.lastname: Chen
authors.affiliation: Calimmune Inc. , Los Angeles, California, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Burke
authors.affiliation: Calimmune Pty Ltd , Darlinghurst, New South Wales, Australia.
authors.forename: Geoff P
authors.initials: GP
authors.lastname: Symonds