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Journal of Virology, March 2004, p. 2572-2580, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2572-2580.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Modification to the Capsid of the Adenovirus Vector That Enhances Dendritic Cell Infection and Transgene-Specific Cellular Immune Responses

Stefan Worgall,1,2,{dagger}* Annette Busch,3,{dagger} Michael Rivara,3 David Bonnyay,4 Philip L. Leopold,1 Robert Merritt,1 Neil R. Hackett,3 Peter W. Rovelink,5 Joseph T. Bruder,5 Thomas J. Wickham,5 Imi Kovesdi,5 and Ronald G. Crystal1,3

Department of Genetic Medicine,1 Department of Pediatrics,2 Belfer Gene Therapy Core Facility,3 Weill Medical College of Cornell University, and Rockefeller University, New York, New York,4 GenVec, Inc., Gaithersburg, Maryland5

Received 26 June 2003/ Accepted 14 November 2003

Adenovirus (Ad) gene transfer vectors can be used to transfer and express antigens and function as strong adjuvants and thus are useful platforms for the development of genetic vaccines. Based on the hypothesis that Ad vectors with enhanced infectibility of dendritic cells (DC) may be able to evoke enhanced immune responses against antigens encoded by the vector in vivo, the present study analyzes the vaccine potential of an Ad vector expressing ß-galactosidase as a model antigen and genetically modified with RGD on the fiber knob [AdZ.F(RGD)] to more selectively infect DC and consequently enhance immunity against the ß-galactosidase antigen. Infection of murine DC in vitro with AdZ.F(RGD) showed an eightfold-increased transgene expression following infection compared to AdZ (also expressing ß-galactosidase, but with a wild-type capsid). Binding, cellular uptake, and trafficking in DC were also increased with AdZ.F(RGD) compared to AdZ. To determine whether AdZ.F(RGD) could evoke enhanced immune responses to ß-galactosidase in vivo, C57BL/6 mice were immunized with AdZ.F(RGD) or AdZ subcutaneously via the footpad. Humoral responses with both vectors were comparable, with similar anti-ß-galactosidase antibody levels following vector administration. However, cellular responses to ß-galactosidase were significantly enhanced, with the frequency of CD4+ as well as the CD8+ ß-galactosidase-specific gamma interferon response in cells isolated from the draining lymph nodes increased following immunization with AdZ.F(RGD) compared to Ad.Z (P < 0.01). Importantly, this enhanced cellular immune response of the AdZ.F(RGD) vector was sufficient to evoke enhanced inhibition of the growth of preexisting tumors expressing ß-galactosidase: BALB/c mice implanted with the CT26 syngeneic ß-galactosidase-expressing colon carcinoma cell line and subsequently immunized with AdZ.F(RGD) showed decreased tumor growth and improved survival compared to mice immunized with AdZ. These data demonstrate that addition of an RGD motif to the Ad fiber knob increases the infectibility of DC and leads to enhanced cellular immune responses to the Ad-transferred transgene, suggesting that the RGD capsid modification may be useful in developing Ad-based vaccines.

* Corresponding author. Mailing address: Department of Genetic Medicine, Weill Medical College of Cornell University, 515 East 71st St., S-1000, New York, NY 10021. Phone: (212) 746-2258. Fax: (212) 746-8383. E-mail: geneticmedicine{at}med.cornell.edu.

{dagger} Both authors contributed equally to this paper.

Journal of Virology, March 2004, p. 2572-2580, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2572-2580.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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