Constitutive expression of the adenovirus E3-14.7K protein does not prolong adenovirus vector DNA persistence but protects mice against lipopolysaccharide-induced acute hepatitis.
First-generation adenovirus vectors, deleted in the E1 and E3 regions of the genome, induce a strong inflammatory response that affects persistence of vector DNA in transduced organs and causes toxicity in the host. Wild-type adenovirus encodes a number of proteins that are nonessential for viral propagation in vitro but that dampen the inflammatory and immune responses mounted by the host during infection. The adenovirus E3 region-encoded 14.7K protein inhibits tumor necrosis factor alpha (TNF-alpha)-induced apoptosis and arachidonic acid synthesis. To evaluate the impact of constitutive expression of the 14.7K protein on vector-induced pathology, toxicity, and DNA persistence, we constructed vectors that contain a cytomegalovirus promoter-driven 14.7K expression cassette. Although these vectors inhibit TNF-alpha-induced apoptosis in vitro, they do not show better vector DNA persistence, or lower inflammation or pathology than E3-deleted first-generation vector in mouse models. However, the 14.7K protein is functional in mice because animals injected intravenously with a 14.7K-constitutive vector were fully protected against a lethal dose of lipopolysaccharide 5 days after vector administration. These results open new applications for the E3-encoded 14.7K protein, which can be used to protect organs against inflammatory reactions and TNF-alpha-mediated apoptosis.
Gantzer
Murielle
M
Transgene, 67082 Strasbourg Cedex, France.
Spitz
Estelle
E
Accard
Nathalie
N
Rooke
Ronald
R
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D017503:Adenovirus E3 Proteins / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005822:Genetic Vectors / Q000276:immunology / Q000633:toxicity; D006520:Hepatitis, Animal / Q000517:prevention & control*; D006801:Humans; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D017503:Adenovirus E3 Proteins; C505032:CFTR protein, human; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator