Adenovirus capsid-display of the retro-oriented human complement inhibitor DAF reduces Ad vector-triggered immune responses in vitro and in vivo

Sergey S. Seregin, Yasser A. Aldhamen, Daniel M. Appledorn, Zachary C. Hartman, Nathan Schuldt, Jeannine Scott, Sarah Godbehere, Haixiang Jiang, Michael M. Frank, Andrea Amalfitano

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Adenovirus (Ad) vectors are widely used in human clinical trials. However, at higher dosages, Ad vector-triggered innate toxicities remain a major obstacle to many applications. Ad interactions with the complement system significantly contribute to innate immune responses in several models of Ad-mediated gene transfer. We constructed a novel class of Ad vectors, genetically engineered to "capsiddisplay" native and retro-oriented versions of the human complement inhibitor decayaccelerating factor (DAF), as a fusion protein from the C-terminus of the Ad capsid protein IX. In contrast to conventional Ad vectors, DAF-displaying Ads dramatically minimized complement activation in vitro and complement-dependent immune responses in vivo. DAF-displayingAds did not trigger thrombocytopenia, minimized endothelial cell activation, and had diminished inductions of proinflammatory cytokine and chemokine responses. The retro-oriented display of DAF facilitated the greatest improvements in vivo, with diminished activation of innate immune cells, such as dendritic and natural killer cells. In conclusion, Ad vectors can capsid-display proteins in a manner that not only retains the functionality of the displayed proteins but also potentially can be harnessed to improve the efficacy of this important gene transfer platform for numerous gene transfer applications.

Original languageEnglish (US)
Pages (from-to)1669-1677
Number of pages9
JournalBlood
Volume116
Issue number10
DOIs
StatePublished - Sep 9 2010
Externally publishedYes

Bibliographical note

Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.

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