Adenovirus Serotype 5 Fiber Shaft InfluencesIn VivoGene Transfer in Mice
| Autor: | Jin Kim, Michael Kaleko, Jennifer Marshall-Neff, Theodore Smith, Susan C. Stevenson, Neeraja Idamakanti, Kathy Mulgrew, Michele Rollence, Glen R. Nemerow |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Coxsackie and Adenovirus Receptor-Like Membrane Protein Integrins viruses Amino Acid Motifs Blotting Western Genetic Vectors Integrin Gene delivery Biology Adenoviridae Cell Line Mice chemistry.chemical_compound Transduction (genetics) Transduction Genetic In vivo Genetics Animals Humans Receptor Molecular Biology Cells Cultured Glycosaminoglycans chemistry.chemical_classification Virion Heparan sulfate beta-Galactosidase Molecular biology Amino acid Mice Inbred C57BL chemistry Cell culture Mutation Hepatocytes biology.protein Receptors Virus Molecular Medicine Capsid Proteins Oligopeptides |
| Zdroj: | Human Gene Therapy. 14:777-787 |
| ISSN: | 1557-7422 1043-0342 |
| Popis: | Adenoviral vectors used in gene therapy are predominantly derived from adenovirus serotype 5 (Ad5), which infects a broad range of cells. Ad5 cell entry involves interactions with the coxsackie-adenovirus receptor (CAR) and integrins. To assess these receptors in vivo, we mutated amino acid residues in fiber and penton that are involved in receptor interaction and showed that CAR and integrins play a minor role in hepatic transduction but that integrins can influence gene delivery to other tissues. These data suggest that an alternative entry pathway exists for hepatocyte transduction in vivo that is more important than CAR or integrins. In vitro data suggest a role for heparan sulfate glycosaminoglycans (HSG) in adenovirus transduction. The role of the fiber shaft in liver uptake was examined by introducing specific amino acid changes into a putative HSG-binding motif contained within the shaft or by preparing fiber shaft chimeras between Ad5 and Ad35 fibers. Results were obtained that demonstrate that the Ad5 fiber shaft can influence gene transfer both in vitro and to the liver in vivo. These observations indicate that the currently accepted two-step entry pathway, which involves CAR and integrins, described for adenoviral infection in vitro, is not used for hepatic gene transfer in vivo. In contrast, alpha(v) integrins influence gene delivery to the lung, spleen, heart, and kidney. The detargeted vector constructs described here may provide a foundation for the development of targeted adenoviral vectors. |
| Databáze: | OpenAIRE |
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