Modulation of the Inflammatory Properties and Hepatotoxicity of Recombinant Adenovirus Vectors by the Viral E4 Gene Products
| Autor: | Dalila Ali Hadji, Fabienne Stoeckel, Dominique Dreyer, Jacqueline Kintz, Linda Grave, Majid Mehtali, Bernard Louis, A Dieterle, Monika Lusky, M. Christ |
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| Rok vydání: | 2000 |
| Předmět: |
Transgene
Genetic enhancement Genetic Vectors Cystic Fibrosis Transmembrane Conductance Regulator Biology Recombinant virus medicine.disease_cause Adenoviridae Mice Open Reading Frames In vivo Genetics medicine Animals Humans Transgenes Vector (molecular biology) Molecular Biology Liver injury Mice Inbred BALB C Gene Transfer Techniques medicine.disease Virology Molecular biology Mice Inbred C57BL Liver Injections Intravenous Toxicity Mice Inbred CBA Molecular Medicine Female Chemical and Drug Induced Liver Injury Gene Deletion Adenovirus E4 Proteins |
| Zdroj: | Human Gene Therapy. 11:415-427 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/10430340050015888 |
| Popis: | Liver toxicity and inflammation were assessed in C57BL/6, CBA, and BALB/c mice injected intravenously with a series of recombinant adenoviruses deleted simultaneously in E1/E3, in E1/E3/E2A, or in E1/E3/E4. All vectors were either devoid of transgenes or carried in E1 the human CFTR cDNA under the control of the CMV promoter. Injection of the E1/E3-deleted vector induced a significant liver dystrophy and inflammatory responses that were accompanied by an increased serum transaminase concentration. The vector toxicity remained elevated on additional deletion of the E2A gene and was further enhanced when hCFTR was expressed. In contrast, additional deletion of E4 led to a reduction in hepatotoxicity, suggesting an active role of E4 gene products in liver injury. However, deletion of E4 also led to a loss of transgene expression. To identify the individual E4 product(s) involved in liver toxicity and in the regulation of transgene expression, a series of isogenic E1/E3-deleted vectors, with or without the hCFTR transgene, and containing various combinations of functional E4 open reading frames (ORFs), were evaluated in vitro and in vivo. We demonstrate that liver injury was markedly reduced with vectors containing either ORF3 alone or ORF3,4 while vectors containing ORF4, ORF6,7 or ORF3,6,7 still displayed elevated hepatotoxicity and inflammatory responses. Moreover, transgene expression was restored when ORF3,4 or ORF3,6,7 was retained in the vector. These results highlight the importance of the E4 gene products in the design of improved in vivo gene transfer vectors. |
| Databáze: | OpenAIRE |
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