CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors' genome.
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.
1] Department of Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA [2] School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA [3] Department of Immune Cell Development and Host Defense, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Te-Lang
TL
Wu
1] Department of Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA [2] Department of Medicine, Kingsbrook Jewish Medical Center, Brooklyn, New York, USA.
Hua
H
Li
Department of Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Susan M
SM
Faust
1] Department of Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA [2] School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Emily
E
Chi
Department of Pediatrics, The Children's Hospital of Philadelphia, Center for Cellular and Molecular Therapeutics, Philadelphia, Pennsylvania, USA.
Shangzhen
S
Zhou
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Fraser
F
Wright
Department of Pediatrics, The Children's Hospital of Philadelphia and Howard Hughes Medical Institute, Philadelphia, Pennsylvania, USA.
Katherine A
KA
High
Department of Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Hildegund C J
HC
Ertl
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002213:Capsid / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology* / Q000592:standards; D016678:Genome; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D011786:Quality Control; D037182:T-Cell Antigen Receptor Specificity; D014161:Transduction, Genetic
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte