title: Serotype-specific Binding Properties and Nanoparticle Characteristics Contribute to the Immunogenicity of rAAV1 Vectors.
abstract: The immunogenic properties of recombinant adeno-associated virus (rAAV) gene transfer vectors remain incompletely characterized in spite of their usage as gene therapy vectors or as vaccines. Molecular interactions between rAAV and various types of antigen-presenting cells (APCs), as well as the impact of these interactions on transgene or capsid-specific immunization remain unclear. We herein show that binding motifs recognized by the capsid and which determine the vector tissue tropism are also critical for key immune activation processes. Using rAAV capsid serotype 1 (rAAV1) vectors which primary receptors on target cells are α2,3 and α2,6 N-linked sialic acids, we show that sialic acid-dependent binding of rAAV1 on APCs is essential to trigger CD4(+) T-cell responses by increasing rAAV1 uptake and contributing to antigenic presentation of both the capsid and transgene product although this involves different APCs. In addition, the nanoparticulate structure of the vector in itself appears to be sufficient to trigger mobilization and activation of some APCs. Therefore, combinations of structural and of serotype-specific cell-targeting properties of rAAV1 determine its complex immunogenicity. These findings may be useful to guide a selection of rAAV variants depending on the intended level of immunogenicity for either gene therapy or vaccination applications.
authors.affiliation: Inserm, U951, "Integrare" research unit, R&D department, Genethon, Evry, F91002 France; University of Evry, UMR_S951, Evry, F91002 France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Ferrand
authors.affiliation: Inserm, U951, "Integrare" research unit, R&D department, Genethon, Evry, F91002 France; University of Evry, UMR_S951, Evry, F91002 France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Da Rocha
authors.affiliation: Inserm, U951, "Integrare" research unit, R&D department, Genethon, Evry, F91002 France; University of Evry, UMR_S951, Evry, F91002 France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Corre
authors.affiliation: Inserm, U951, "Integrare" research unit, R&D department, Genethon, Evry, F91002 France; University of Evry, UMR_S951, Evry, F91002 France. Electronic address: galy@genethon.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.affiliation: Inserm, U951, "Integrare" research unit, R&D department, Genethon, Evry, F91002 France; University of Evry, UMR_S951, Evry, F91002 France. Electronic address: fboisgerault@genethon.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Boisgerault
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002213:Capsid / Q000276:immunology; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D007273:Injections, Intramuscular; D037102:Lectins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D054118:Nanospheres / Q000737:chemistry / Q000821:virology; D025341:Principal Component Analysis; D065288:Serogroup; D019076:Transgenes; D014614:Vaccines, Synthetic / Q000821:virology
chemical_list: D037102:Lectins; D014614:Vaccines, Synthetic