Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets
Abstract
Liver toxicity observed in a clinical trial of adeno-associated virus serotype 2 (AAV2) delivered systemically to patients with hemophilia was ascribed to killing of vector-transduced hepatocytes by capsid-specific T cells. This study evaluated the biology of T cell activation in response to AAV capsids in murine models. CD8(+) T cell epitopes were mapped to capsids from AAV2, AAV7, and AAV8. A tetramer generated in response to a dominant capsid epitope in BALB/c mice was shared between these AAV serotypes. Administration of AAV2 vector resulted in the activation of capsid-specific CD8(+) T cells as evidenced by binding to tetramer and production of capsid-induced interferon-gamma expression this was not observed with the AAV7 and AAV8 vectors. CD8(+) T cells specific to AAV2 capsids demonstrate functional cytolytic activity in vivo to peptide-loaded target cells. The frequency of capsid-specific T cells was much higher in liver than in blood or spleen. The performance of liver-directed AAV-mediated gene transfer was not diminished in animals with high levels of pre-existing capsid-specific T cells. We conclude that cross-presentation of AAV capsids does result in activation of cytotoxic T lymphocytes (CTLs) in a serotype-specific manner; however, there is no evidence that vector-transduced hepatocytes are targets for CTL effector activity.
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CD8+ T cell responses against input capsid may develop faster in mice than against the transgene product.
“CD8+ T cell responses against input capsid may develop faster in mice than against the transgene product.25,65”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [65]
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- Authors
- Wang, L., Figueredo, J., Calcedo, R., Lin, J., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2007-03
- Volume
- 18
- Issue
- 3
- Pages
- 185-194
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- OpenAlex
- W1971410862
- Cited by
- 113
- References
- 20
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 1 · 2017: 8 · 2016: 4 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 5
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Emory University
- National Heart, Lung, and Blood Institute (P01HL059407)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK 47757, P30DK047757, P30-DK-47757-PILOT)
- 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
- AAV2, AAV capsid, cross-presentation, cytotoxic T lymphocytes, CTL epitopes, AAV8, hepatotoxicity, hepatocyte lysis, interferon-gamma, tetramer, liver-directed gene transfer, hemophilia
- MeSH terms
- Dependovirus, Amino Acid Sequence, Animals, Capsid, Cell Movement, Cytotoxicity Tests, Immunologic, Genetic Vectors, Liver, Lymphocyte Activation, Molecular Sequence Data, T-Lymphocytes, Cytotoxic, Transduction, Genetic, Epitope Mapping, Epitopes, T-Lymphocyte, Hepatocytes, Cross-Priming, Mice
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