CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors' genome
Open accessAbstract
Self-complementary adeno-associated viral (AAV) vectors expressing human factor IX (hF.IX) have achieved transient or sustained correction of hemophilia B in human volunteers. High doses of AAV2 or AAV8 vectors delivered to the liver caused in several patients an increase in transaminases accompanied by a rise in AAV capsid-specific T cells and a decrease in circulating hF.IX levels suggesting immune-mediated destruction of vector-transduced cells. Kinetics of these adverse events differed in patients receiving AAV2 or AAV8 vectors causing rise in transaminases at 3 versus 8 weeks after vector injection, respectively. To test if CD8+ T cells to AAV8 vectors, which are similar to AAV2 vectors are fully-gutted vectors and thereby fail to encode structural viral proteins, could cause damage at this late time point, we tested in a series of mouse studies how long major histocompatibility (MHC) class I epitopes within AAV8 capsid can be presented to CD8+ T cells. Our results clearly show that depending on the vectors' genome, CD8+ T cells can detect such epitopes on AAV8's capsid for up to 6 months indicating that the capsid of AAV8 degrades slowly in mice.
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AAV8 does not elicit a CD8+ T cell response against capsid in mice, and the vector dose was too low to generate such a response.
“However, this does not apply here because AAV8 does not elicit a CD8+ T cell response against capsid in mice and because the vector dose was anyhow too low to generate such a response.25,66,67”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [67]
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- Authors
- Wu, T.-L., Li, H., Faust, S. M., Chi, E., Zhou, S., Wright, F., High, K. A., & Ertl, H. C.
- Affiliations
- The Wistar Institute (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Ertl, Hildegund CJ
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 22
- Issue
- 1
- Pages
- 42-51
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3978806
- OpenAlex
- W1964969249
- Cited by
- 38
- References
- 29
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 2 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 4
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL078810)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus 8, AAV capsid, CD8+ T cells, MHC class I epitopes, self-complementary AAV vectors, gene delivery vectors, hemophilia B, factor IX, liver gene transfer
- MeSH terms
- Dependovirus, Animals, Capsid, Genetic Vectors, Humans, Immunologic Memory, Lymphocyte Activation, Male, Quality Control, Transduction, Genetic, Genome, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Capsid Proteins, T-Cell Antigen Receptor Specificity, Mice
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