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Journal of Virology, December 1998, p. 9706-9713, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

An Adenovirus Vector with Genetically Modified Fibers Demonstrates Expanded Tropism via Utilization of a Coxsackievirus and Adenovirus Receptor-Independent Cell Entry Mechanism

Igor Dmitriev, Victor Krasnykh, C. Ryan Miller, Minghui Wang, Elena Kashentseva, Galina Mikheeva, Natalya Belousova, and David T. Curiel*

Gene Therapy Program, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300

Received 11 June 1998/Accepted 2 September 1998

Recombinant adenoviruses (Ad) have become the vector system of choice for a variety of gene therapy applications. However, the utility of Ad vectors is limited due to the low efficiency of Ad-mediated gene transfer to cells expressing marginal levels of the coxsackievirus and adenovirus receptor (CAR). In order to achieve CAR-independent gene transfer by Ad vectors in clinically important contexts, we proposed modification of viral tropism via genetic alterations to the viral fiber protein. We have shown that incorporation of an Arg-Gly-Asp (RGD)-containing peptide in the HI loop of the fiber knob domain results in the ability of the virus to utilize an alternative receptor during the cell entry process. We have also demonstrated that due to its expanded tissue tropism, this novel vector is capable of efficient transduction of primary tumor cells. An increase in gene transfer to ovarian cancer cells of 2 to 3 orders of magnitude was demonstrated by the vector, suggesting that recombinant Ad containing fibers with an incorporated RGD peptide may be of great utility for treatment of neoplasms characterized by deficiency of the primary Ad type 5 receptor.

* Corresponding author. Mailing address: Gene Therapy Program, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294-3300. Phone: (205) 934-8627. Fax: (205) 975-7476. E-mail: david.curiel{at}ccc.uab.edu.

Journal of Virology, December 1998, p. 9706-9713, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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