Vector uncoating limits adeno-associated viral vector-mediated transduction of human dendritic cells and vector immunogenicity - Archive ouverte HAL Access content directly
Journal Articles Scientific Reports Year : 2019

Vector uncoating limits adeno-associated viral vector-mediated transduction of human dendritic cells and vector immunogenicity

, , (1) , , , (2) , (3) , (4) , (1) , (5)
1
2
3
4
5
Axel Rossi
  • Function : Author
Léa Dupaty
  • Function : Author
Liang Zhang
  • Function : Author
Célia Gallien
  • Function : Author
Margarete Odenthal
  • Function : Author
  • PersonId : 910917
Anna Salvetti

Abstract

AAV vectors poorly transduce Dendritic cells (DC), a feature invoked to explain AAV's low immunogenicity. However, the reason for this non-permissiveness remained elusive. Here, we performed an in-depth analysis using human monocyte-derived immature DC (iDC) as model. iDC internalized AAV vectors of various serotypes, but even the most efficient serotype failed to transduce iDC above background. Since AAV vectors reached the cell nucleus, we hypothesized that AAV's intracellular processing occurs suboptimal. On this basis, we screened an AAV peptide display library for capsid variants more suitable for DC transduction and identified the I/VSS family which transduced DC with efficiencies of up to 38%. This property correlated with an improved vector uncoating. To determine the consequence of this novel feature for AAV's in vivo performance, we engineered one of the lead candidates to express a cytoplasmic form of ovalbumin, a highly immunogenic model antigen, and assayed transduction efficiency as well as immunogenicity. The capsid variant clearly outperformed the parental serotype in muscle transduction and in inducing antigen-specific humoral and T cell responses as well as anti-capsid CD8 + T cells. Hence, vector uncoating represents a major barrier hampering AAV vector-mediated transduction of DC and impacts on its use as vaccine platform.
Fichier principal
Vignette du fichier
s41598-019-40071-1.pdf (2.2 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Loading...

Dates and versions

hal-02375623 , version 1 (22-11-2019)

Identifiers

Cite

Axel Rossi, Léa Dupaty, Ludovic Aillot, Liang Zhang, Célia Gallien, et al.. Vector uncoating limits adeno-associated viral vector-mediated transduction of human dendritic cells and vector immunogenicity. Scientific Reports, 2019, 9 (1), ⟨10.1038/s41598-019-40071-1⟩. ⟨hal-02375623⟩
104 View
102 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More