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Journal of Virology, September 2002, p. 8621-8631, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8621-8631.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Modulation of Adenovirus Vector Tropism via Incorporation of Polypeptide Ligands into the Fiber Protein

Natalya Belousova,1 Valentina Krendelchtchikova,1 David T. Curiel,1 and Victor Krasnykh1,2*

Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and Gene Therapy Center, University of Alabama at Birmingham,1 VectorLogics, Inc., Birmingham, Alabama 352942

Received 21 March 2002/ Accepted 6 June 2002

The efficacy of adenovirus (Ad)-based gene therapy might be significantly improved if viral vectors capable of tissue-specific gene delivery could be developed. Previous attempts to genetically modify the tropism of Ad vectors have been only partially successful, largely due to the limited repertoire of ligands that can be incorporated into the Ad capsid. Early studies identified stringent size limitations imposed by the structure of the Ad fiber protein on ligands incorporated into its carboxy terminus and thus limited the range of potential ligand candidates to short peptides. We have previously identified the HI loop of the fiber knob domain as a preferred site for the incorporation of targeting ligands and hypothesized that the structural properties of this loop would allow for the insertion of a wide variety of ligands, including large polypeptide molecules. In the present study we have tested this hypothesis by deriving a family of Ad vectors whose fibers contain polypeptide inserts of incrementally increasing lengths. By assessing the levels of productivity and infectivity and the receptor specificities of the resultant viruses, we show that polypeptide sequences exceeding by 50% the size of the knob domain can be incorporated into the fiber with only marginal negative consequences on these key properties of the vectors. Our study has also revealed a negative correlation between the size of the ligand used for vector modification and the infectivity and yield of the resultant virus, thereby predicting the limits beyond which further enlargement of the fiber knob would not be compatible with the virion's integrity.

* Corresponding author. Mailing address: 901 19th St. South, BMR II 404, Birmingham, AL 35294. Phone: (205) 975-2898. Fax: (205) 975-8565. E-mail: Victor.Krasnykh{at}ccc.uab.edu.

Journal of Virology, September 2002, p. 8621-8631, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8621-8631.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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