TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

Bottermann, M. et al. (2018) TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination. Proceedings of the National Academy of Sciences of the United States of America, 115(41), pp. 10440-10445. (doi:10.1073/pnas.1806314115) (PMID:30209217) (PMCID:PMC6187179)

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Abstract

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hirst, Jack and Hutchinson, Dr Edward
Authors: Bottermann, M., Foss, S., van Tienen, L. M., Vaysburd, M., Cruickshank, J., O'Connell, K., Clark, J., Mayes, K., Higginson, K., Hirst, J. C., McAdam, M. B., Slodkowicz, G., Hutchinson, E., Kozik, P., Andersen, J. T., and James, L. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:12 September 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 115(41): 10440-10445
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
703851Functional investigations of the influenza virus proteomeEdward HutchinsonMedical Research Council (MRC)MR/N008618/1MVLS III - CENTRE FOR VIRUS RESEARCH