Constitutive expression of the adenovirus E3-14.7K protein does not prolong adenovirus vector DNA persistence but protects mice against lipopolysaccharide-induced acute hepatitis.
Hum Gene Ther
; 13(8): 921-33, 2002 May 20.
Article
em En
| MEDLINE
| ID: mdl-12031125
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Adenoviridae
/
Proteínas E3 de Adenovirus
/
Vetores Genéticos
/
Hepatite Animal
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article