Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors

Adeno-associated virus (AAV) vectors are effective gene delivery vehicles mediating long-lasting transgene expression. Data from a clinical trial of AAV2-mediated hepatic transfer of the Factor IX gene (F9) into hemophilia B subjects suggests that CTL responses against AAV capsid can eliminate trans...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2009-06, Vol.119 (6), p.1688-1695
Main Authors: Pien, Gary C, Basner-Tschakarjan, Etiena, Hui, Daniel J, Mentlik, Ashley N, Finn, Jonathan D, Hasbrouck, Nicole C, Zhou, Shangzhen, Murphy, Samuel L, Maus, Marcela V, Mingozzi, Federico, Orange, Jordan S, High, Katherine A
Format: Article
Language:English
Subjects:
Antigen presentation
Antigen Presentation - immunology
Biomedical research
Capsid Proteins - immunology
Capsid Proteins - metabolism
Care and treatment
Cell Line
Clinical trials
Cloning
Cytotoxicity, Immunologic - immunology
Dependovirus - genetics
Flow cytometry
Gene therapy
Genetic aspects
Genetic transformation
Genetic Vectors - genetics
Health aspects
Hemophilia
Hepatocytes - cytology
Hepatocytes - immunology
Hepatocytes - metabolism
Histocompatibility Antigens - immunology
Humans
Liver cells
Lymphocytes
Methods
Microscopy
Peptides
Physiological aspects
Protein Multimerization
Reagents
Receptors, Antigen, T-Cell - immunology
Risk factors
Solubility
Substrate Specificity
T cells
T-Lymphocytes, Cytotoxic - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Adeno-associated virus (AAV) vectors are effective gene delivery vehicles mediating long-lasting transgene expression. Data from a clinical trial of AAV2-mediated hepatic transfer of the Factor IX gene (F9) into hemophilia B subjects suggests that CTL responses against AAV capsid can eliminate transduced hepatocytes and prevent long-term F9 expression. However, the capacity of hepatocytes to present AAV capsid-derived antigens has not been formally demonstrated, nor whether transduction by AAV sensitizes hepatocytes for CTL-mediated destruction. To investigate the fate of capsids after transduction, we engineered a soluble TCR for the detection of capsid-derived peptide:MHC I (pMHC) complexes. TCR multimers exhibited antigen and HLA specificity and possessed high binding affinity for cognate pMHC complexes. With this reagent, capsid pMHC complexes were detectable by confocal microscopy following AAV-mediated transduction of human hepatocytes. Although antigen presentation was modest, it was sufficient to flag transduced cells for CTL-mediated lysis in an in vitro killing assay. Destruction of hepatocytes was inhibited by soluble TCR, demonstrating a possible application for this reagent in blocking undesirable CTL responses. Together, these studies provide a mechanism for the loss of transgene expression and transient elevations in aminotransferases following AAV-mediated hepatic gene transfer in humans and a potential therapeutic intervention to abrogate these limitations imposed by the host T cell response.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI36891