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

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 an...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-10, Vol.115 (41), p.10440-10445
Main Authors: Bottermann, Maria, Foss, Stian, van Tienen, Laurens M., Vaysburd, Marina, Cruickshank, James, O’Connell, Kevin, Clark, Jessica, Mayes, Keith, Higginson, Katie, Hirst, Jack C., McAdam, Martin B., Slodkowicz, Greg, Hutchinson, Edward, Kozik, Patrycja, Andersen, Jan Terje, James, Leo C.
Format: Article
Language:English
Subjects:
Adenoviridae - immunology
Adenoviridae Infections - genetics
Adenoviridae Infections - immunology
Adenoviridae Infections - therapy
Adenoviruses
Animals
Antibodies
Antibodies - immunology
Biological Sciences
Blocking
Cytotoxicity
Data processing
Fibrosarcoma - genetics
Fibrosarcoma - immunology
Fibrosarcoma - therapy
Gene expression
Gene therapy
Gene transfer
Gene Transfer Techniques
Genetic Therapy
Genetic Vectors
Immune response
Immune system
Immunity
Immunization
Immunoglobulins
Infectious diseases
Influenza
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred C57BL
Mice, Knockout
Point mutation
Ribonucleoproteins - physiology
Studies
Transcription
Transgenes
Tumor Cells, Cultured
Vaccination
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1806314115