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Journal of Virology, December 2006, p. 12324-12331, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01331-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Adenovirus Fiber Shaft Contains a Trimerization Element That Supports Peptide Fusion for Targeted Gene Delivery ^,

Jiali Li,¹ Sonya Lad,¹ Guang Yang,¹ Yunping Luo,¹ Milena Iacobelli-Martinez,¹ F. James Primus,² Ralph A. Reisfeld,¹ and Erguang Li^1*

Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,¹ Department of Pathology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232²

Received 24 June 2006/ Accepted 26 September 2006

Adenoviral (Ad) vectors have been widely used in human gene therapy clinical trials. However, their application has frequently been restricted by the unfavorable expression of cell surface receptors critical for Ad infection. Infections by Ad2 and Ad5 are largely regulated by the elongated fiber protein that mediates its attachment to a cell surface receptor, coxsackie and adenovirus receptor (CAR). The fiber protein is a homotrimer consisting of an N-terminal tail, a long shaft, and a C-terminal knob region that is responsible for high-affinity receptor binding and Ad tropism. Consequently, the modification of the knob region, including peptide insertion and C-terminal fusion of ligands for cell surface receptors, has become a major research focus for targeting gene delivery. Such manipulation tends to disrupt fiber assembly since the knob region contains a stabilization element for fiber trimerization. We report here the identification of a novel trimerization element in the Ad fiber shaft. We demonstrate that fiber fragments containing the N-terminal tail and shaft repeats formed stable trimers that assembled onto Ad virions independently of the knob region. This fiber shaft trimerization element (FSTE) exhibited a capacity to support peptide fusion. We showed that Ad, modified with a chimeric protein by direct fusion of the FSTE with a growth factor ligand or a single-chain antibody, delivered a reporter gene selectively. Together, these results indicate that the shaft region of Ad fiber protein contains a trimerization element that allows ligand fusion, which potentially broadens the basis for Ad vector development.

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* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-2206. Fax: (858) 784-8239. E-mail: erguang{at}scripps.edu.

Published ahead of print on 4 October 2006.

This is manuscript 16516-IMM from The Scripps Research Institute.

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Journal of Virology, December 2006, p. 12324-12331, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01331-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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