Universität zu Köln

Rossi, Axel, Dupaty, Lea, Aillot, Ludovic, Zhang, Liang, Gallien, Celia, Hallek, Michael, Odenthal, Margarete, Adriouch, Sahil, Salvetti, Anna ORCID: 0000-0003-2007-8350 and Buening, Hildegard (2019). Vector uncoating limits adenoassociated viral vector-mediated transduction of human dendritic cells and vector immunogenicity. Sci Rep, 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rossi, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Dupaty, Lea UNSPECIFIED UNSPECIFIED UNSPECIFIED Aillot, Ludovic UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Liang UNSPECIFIED UNSPECIFIED UNSPECIFIED Gallien, Celia UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Adriouch, Sahil UNSPECIFIED UNSPECIFIED UNSPECIFIED Salvetti, Anna UNSPECIFIED orcid.org/0000-0003-2007-8350 UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-154178
DOI:	10.1038/s41598-019-40071-1
Journal or Publication Title:	Sci Rep
Volume:	9
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VIRUS TYPE-2; HEPARAN-SULFATE; CROSS-PRESENTATION; IMMUNE-RESPONSES; MATURATION; EXPRESSION; GENOMES; ANTIGEN; IDENTIFICATION; TRAFFICKING Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15417