Adeno-associated virus-mediated gene transfer to nonhuman primate liver can elicit destructive transgene-specific T cell responses.
Gene transfer to murine liver with vectors based on novel adeno-associated virus (AAV) serotypes is efficient, stable, and safe even in the setting of antigenic transgene products. We undertook a study in cynomolgus macaques to evaluate the relevance of these findings to primates. The vectors were based on AAV serotype 7 and expressed green fluorescence protein (GFP) from the cytomegalovirus enhanced beta-actin promoter in both single-stranded and self-complementary genomes. Transduction efficiencies from the single-stranded vectors were similar to those observed in mice, although there was no advantage in primates with the self-complementary vectors. Primates elicited vibrant cytotoxic T cell responses to GFP that correlated with hepatitis and loss of transgene expression. There was no evidence of T cell activation in response to the AAV capsid. These studies indicate that under some conditions primates may activate more robust T cell responses to transgene products than is observed in mice.
Gao
Guangping
G
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-3403, USA.
Wang
Qiang
Q
Calcedo
Roberto
R
Mays
Lauren
L
Bell
Peter
P
Wang
Lili
L
Vandenberghe
Luk H
LH
Grant
Rebecca
R
Sanmiguel
Julio
J
Furth
Emma E
EE
Wilson
James M
JM
D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D008252:Macaca fascicularis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019076:Transgenes / Q000235:genetics / Q000276:immunology* / Q000502:physiology
D036022:Capsid Proteins; D049452:Green Fluorescent Proteins