期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 101, 期 16, 页码 6188-6193出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0400542101
关键词
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资金
- NCI NIH HHS [T32 CA09385, T32 CA009385, CA68485, P30 CA068485] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007751, T32 HL07751] Funding Source: Medline
- NIAID NIH HHS [R01 AI038296, R01 AI43588, P30 AI036211, R01 AI042588, AI36211] Funding Source: Medline
- NIDDK NIH HHS [P30 DK020593, DK056338, DK20593, P30 DK056338] Funding Source: Medline
- NIGMS NIH HHS [R01 GM67853, R01 GM067853] Funding Source: Medline
The utility of adenovirus (Ad) vectors for gene transduction can be limited by receptor specificity. We developed a gene-delivery vehicle in which the potent Ad5 vector was genetically reengineered to display the mucosal-targeting sigma1 protein of reovirus type 3 Dearing (T3D). A sigma1 construct containing all but a small virion-anchoring domain was fused to the N-terminal 44 aa of Ad5 fiber. This chimeric attachment protein Fibtail-T3Dsigma1 forms trimers and assembles onto Ad virions. Fibtail-T3Dsigma1 was recombined into the Ad5 genome, replacing sequences encoding wild-type fiber. The resulting vector, Ad5-T3Dsigma1, expresses Fibtail-T3Dsigma1 and infects Chinese hamster ovary cells transfected with human or mouse homologs of the reovirus receptor, junctional adhesion molecule 1 (JAM1), but not the coxsackievirus and Ad receptor. Treatment of Caco-2 intestinal epithelial cells with either JAM1-specific antibody or neuraminidase reduced transduction by Ad5T3Dsigma1, and their combined effect decreased transduction by 95%. Ad5-T3Dsigma1 transduces primary cultures of human dendritic cells substantially more efficiently than does Ad5, and this transduction depends on expression of JAM1. These data provide strong evidence that Ad5-T3Dsigma1 can be redirected to cells expressing JAM1 and sialic acid for application as a vaccine vector.
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