title: Lentiviral vectors displaying modified measles virus gp overcome pre-existing immunity in in vivo-like transduction of human T and B cells.
abstract: Gene transfer into quiescent T and B cells is important for gene therapy and immunotherapy approaches. Previously, we generated lentiviral vectors (LVs) pseudotyped with Edmonston (Ed) measles virus (MV) hemagglutinin (H) and fusion (F) glycoproteins (H/F-LVs), which allowed efficient transduction of quiescent human T and B cells. However, a major obstacle in the use of H/F-LVs in vivo is that most of the human population is vaccinated against measles. As the MV humoral immune response is exclusively directed against the H protein of MV, we mutated the two dominant epitopes in H, Noose, and NE. LVs pseudotyped with these mutant H-glycoproteins escaped inactivation by monoclonal antibodies (mAbs) but were still neutralized by human serum. Consequently, we took advantage of newly emerged MV-D genotypes that were less sensitive to MV vaccination due to a different glycosylation pattern. The mutation responsible was introduced into the H/F-LVs, already mutated for Noose and NE epitopes. We found that these mutant H/F-LVs could efficiently transduce quiescent lymphocytes in the presence of high concentrations of MV antibody-positive human serum. Finally, upon incubation with total blood, mimicking the in vivo situation, the mutant H/F-LVs escaped MV antibody neutralization, where the original H/F-LVs failed. Thus, these novel H/F-LVs offer perspectives for in vivo lymphocyte-based gene therapy and immunotherapy.
authors.affiliation: INSERM, U758, Human Virology Laboratory, EVIR Team, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lévy
authors.affiliation: INSERM, U758, Human Virology Laboratory, EVIR Team, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France.
authors.forename: Fouzia
authors.initials: F
authors.lastname: Amirache
authors.affiliation: INSERM, U758, Human Virology Laboratory, EVIR Team, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Costa
authors.affiliation: INSERM, U758, Human Virology Laboratory, EVIR Team, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Frecha
authors.affiliation: Department of Immunology and WHO Collaborating Center for Reference and Research on Measles Infections, Centre de Recherche Public de la Santé, Laboratoire National de Santé, Luxembourg, Luxembourg.
authors.forename: Claude P
authors.initials: CP
authors.lastname: Muller
authors.affiliation: INSERM, U758, Human Virology Laboratory, Molecular Basis of Paramyxovirus Entry, Lyon, France.
authors.forename: Hasan
authors.initials: H
authors.lastname: Kweder
authors.affiliation: Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France; INSERM, U758, Human Virology Laboratory, Molecular Basis of Paramyxovirus Entry, Lyon, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Buckland
authors.affiliation: INSERM, U758, Human Virology Laboratory, EVIR Team, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France. Electronic address: flcosset@ens-lyon.fr.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: INSERM, U758, Human Virology Laboratory, EVIR Team, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université de Lyon, UCB-Lyon1, Lyon, France. Electronic address: els.verhoeyen@ens-lyon.fr.
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D045744:Cell Line, Tumor; D006224:Cricetinae; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D006031:Glycosylation; D006388:Hemagglutinins / Q000235:genetics / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000628:therapy; D007167:Immunotherapy; D016086:Lentivirus / Q000235:genetics* / Q000276:immunology; D008458:Measles Vaccine / Q000276:immunology; D008459:Measles virus / Q000235:genetics* / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D014161:Transduction, Genetic; D014760:Viral Fusion Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D006388:Hemagglutinins; D008458:Measles Vaccine; D014760:Viral Fusion Proteins