title: Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early-cytokine-stimulated and resting HSCs.
abstract: Hematopoietic stem cell (HSC)-based gene therapy holds promise for the cure of many diseases. The field is now moving toward the use of lentiviral vectors (LVs) as evidenced by 4 successful clinical trials. These trials used vesicular-stomatitis-virus-G protein (VSV-G)-LVs at high doses combined with strong cytokine-cocktail stimulation to obtain therapeutically relevant transduction levels; however, they might compromise the HSC character. Summarizing all these disadvantages, alternatives to VSV-G-LVs are urgently needed. We generated here high-titer LVs pseudotyped with a baboon retroviral envelope glycoprotein (BaEV-LVs), resistant to human complement. Under mild cytokine prestimulation to preserve the HSC characteristics, a single BaEV-LV application at a low dose, resulted in up to 90% of hCD34(+) cell transduction. Even more striking was that these new BaEV-LVs allowed, at low doses, efficient transduction of up to 30% of quiescent hCD34(+) cells, whereas high-dose VSV-G-LVs were insufficient. Importantly, reconstitution of NOD/Lt-SCID/γc(-/-) (NSG) mice with BaEV-LV-transduced hCD34(+) cells maintained these high transduction levels in all myeloid and lymphoid lineages, including early progenitors. This transduction pattern was confirmed or even increased in secondary NSG recipient mice. This suggests that BaEV-LVs efficiently transduce true HSCs and could improve HSC-based gene therapy, for which high-level HSC correction is needed for life-long cure.
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: Anais
authors.initials: A
authors.lastname: Girard-Gagnepain
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: Fouzia
authors.initials: F
authors.lastname: Amirache
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Costa
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: Camille
authors.initials: C
authors.lastname: Lévy
authors.affiliation: Laboratory of Neuroplasticity and Neurotoxins, Institute of Cellular Biology and Neuroscience, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Frecha
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: Floriane
authors.initials: F
authors.lastname: Fusil
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: Didier
authors.initials: D
authors.lastname: Nègre
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5557 Microbial Ecology, Universite Lyon 1, Microbial Dynamics and Viral Transmission, Villeurbanne, France; and.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Lavillette
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France;
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: Centre International de Recherche en Infectiologie, Team Enveloped Viruses, Vectors and Innate Responses, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France; INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe "Contrôle Métabolique des Morts Cellulaires," Nice, France.
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
mesh_terms: D000818:Animals; D018952:Antigens, CD34; D030121:Betaretrovirus / Q000235:genetics*; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008251:Macaca; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins