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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Axel Rossi, Léa Dupaty, Ludovic Aillot, Liang Zhang, Célia Gallien, Michael Hallek, Margarete Odenthal, Sahil Adriouch, Anna Salvetti, Hildegard Büning

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. More... »

PAGES

3631

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-40071-1

DOI

http://dx.doi.org/10.1038/s41598-019-40071-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112568184

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30842485


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