The constitutive expression of the immunomodulatory gp19k protein in E1-, E3- adenoviral vectors strongly reduces the host cytotoxic T cell response against the vector.
The immune response against cells infected by gene therapy vectors may be a major hindrance for gene therapy, destroying infected cells thus limiting the length of exogene expression and quickly eliminating infected cells on repeat administration. Adenoviruses and many other pathogens have evolved strategies for escape from immune surveillance, including the gp19k gene, found in the adenovirus E3 region, known to down-regulate major histocompatibility complex class 1 expression on the cell surface, and thus reduce lysis of the infected cells by cytotoxic T cells. We have constructed an adenoviral vector expressing the genes for beta-galactosidase and gp19k both under the control of constitutive promoters, and compared the capacity of lymphocytes from DBA/2 mice previously injected with the virus or with Ad-beta gal, a virus expressing beta-galactosidase but not gp19k, to lyse target cells infected with various viruses. Lymphocytes raised against Ad-beta gal fail to lyse target cells infected with Ad-beta gal-gp19k significantly, whereas Ad-beta gal infected target cells and a beta-galactosidase expressing cell line are strongly lysed. The administration of Ad-beta gal-gp19k fails to stimulate the proliferation of anti-vector lymphocytes, and thus these lymphocytes show poor cytotoxic activity against Ad-beta gal or Ad-beta gal-gp19k infected cells.
Lee
M G
MG
Laboratoire de Génétique de Virus Oncogènes, URA 1301 CNRS, Institut Gustave Roussy PR2, Villejuif, France.
Abina
M A
MA
Haddada
H
H
Perricaudet
M
M
D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017498:Adenovirus E1 Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017503:Adenovirus E3 Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D012313:RNA / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D017498:Adenovirus E1 Proteins; D017503:Adenovirus E3 Proteins; C084390:E3 glycoprotein 19k, Adenovirus type 7; D011994:Recombinant Proteins; D012313:RNA; D001616:beta-Galactosidase