Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes.
The goal of these studies was to test whether adeno-associated virus (AAV) capsid-specific CD8(+) T cells cause loss of hepatic AAV-mediated gene expression in experimental animals. Mice immunized with adenoviral vectors expressing AAV capsid or with AAV vectors developed CD8(+) T cells in blood, lymphatic tissues, and liver to epitopes shared between AAV2 and AAV8, and serotype-specific neutralizing antibodies. At the height of the T cells' effector phase, mice were infused with a heterologous AAV vector expressing human factor IX under a hepatocyte-specific promoter. Despite the presence of lytic CD8(+) T cells in the liver, hepatic Factor IX expression was sustained and comparable in AAV-preimmune and naïve animals. These results suggest that, in mice, pre-existing CD8(+) T cells to AAV capsid do not affect the longevity of AAV-mediated hepatic gene transfer. These results are in contrast to the outcome of a recent gene therapy trial of hemophilia B patients who were treated by hepatic gene transfer of AAV2 vectors expressing Factor IX. The loss of Factor IX expression, accompanied by a rise in liver enzymes and detectable frequencies of circulating AAV capsid-specific T cells, suggested T-cell-mediated destruction of transduced hepatocytes following reactivation of AAV-specific T cells upon AAV transfer.
Li
Hua
H
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Murphy
Samuel L
SL
Giles-Davis
Wynetta
W
Edmonson
Shyrie
S
Xiang
Zhiquan
Z
Li
Yan
Y
Lasaro
Marcio O
MO
High
Katherine A
KA
Ertl
Hildegund Cj
HC
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002213:Capsid / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology*; D005164:Factor IX / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000276:immunology; D002836:Hemophilia B / Q000235:genetics / Q000276:immunology / Q000628:therapy; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology*; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D014161:Transduction, Genetic
D005164:Factor IX