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Journal of Virology, August 2001, p. 7280-7289, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7280-7289.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Genetic Retargeting of Adenovirus: Novel Strategy Employing "Deknobbing" of the Fiber

Maria K. Magnusson,1,2 Saw See Hong,3 Pierre Boulanger,3 and Leif Lindholm1,2,*

Department of Medical Microbiology and Immunology, University of Göteborg,1 and Got-A-Gene AB,2 Göteborg, Sweden, and Laboratoire de Virologie et Pathogénèse Virale, CNRS UMR-5537, Faculté de Médecine RTH Laennec, 69372 Lyon Cedex, France3

Received 27 December 2000/Accepted 23 May 2001

For efficient and versatile use of adenovirus (Ad) as an in vivo gene therapy vector, modulation of the viral tropism is highly desirable. In this study, a novel method to genetically alter the Ad fiber tropism is described. The knob and the last 15 shaft repeats of the fiber gene were deleted and replaced with an external trimerization motif and a new cell-binding ligand, in this case the integrin-binding motif RGD. The corresponding recombinant fiber retained the basic biological functions of the natural fiber, i.e., trimerization, nuclear import, penton formation, and ligand binding. The recombinant fiber bound to integrins but failed to react with antiknob antibody. For virus production, the recombinant fiber gene was rescued into the Ad genome at the exact position of the wild-type (WT) fiber to make use of the native regulation of fiber expression. The recombinant virus Ad5/FibR7-RGD yielded plaques on 293 cells, but the spread through the monolayer was two to three times delayed compared to WT, and the ratio of infectious to physical particles was 20 times lower. Studies on virus tropism showed that Ad5/FibR7-RGD was able to infect cells which did not express the coxsackie-adenovirus receptor (CAR), but did express integrins. Ad5/FibR7-RGD virus infectivity was unchanged in the presence of antiknob antibody, which neutralized the WT virus. Ad5/FibR7-RGD virus showed an expanded tropism, which is useful when gene transfer to cells not expressing CAR is needed. The described method should also make possible the construction of Ad genetically retargeted via ligands other than RGD.

* Corresponding author. Mailing address: Department of Medical Microbiology & Immunology, University of Göteborg, P.O. Box 435, SE-405 30 Göteborg, Sweden. Phone: 46-31-3424693. Fax: 46-31-415608. E-mail: leif.lindholm{at}microbio.gu.se.

Journal of Virology, August 2001, p. 7280-7289, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7280-7289.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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