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Journal of Virology, October 2001, p. 9493-9501, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9493-9501.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Adeno-Associated Virus Type 2-Mediated Transduction of Human Monocyte-Derived Dendritic Cells: Implications for Ex Vivo Immunotherapy

Selvarangan Ponnazhagan,1,2,3,* Gandham Mahendra,1 David T. Curiel,1,2,3,4 and Denise R. Shaw2,3,4

Departments of Pathology1 and Medicine,4 the Gene Therapy Center,2 and the Comprehensive Cancer Center,3 University of Alabama at Birmingham, Birmingham, Alabama 35294

Received 3 May 2001/Accepted 22 June 2001

Dendritic cells (DCs) are pivotal antigen-presenting cells for regulating immune responses. A major focus of contemporary vaccine research is the genetic modification of DCs to express antigens or immunomodulatory molecules, utilizing a variety of viral and nonviral vectors, to induce antigen-specific immune responses that ameliorate disease states as diverse as malignancy, infection, autoimmunity, and allergy. The present study has evaluated adeno-associated virus (AAV) type 2 as a vector for ex vivo gene transfer to human peripheral blood monocyte (MO)-derived DCs. AAV is a nonpathogenic parvovirus that infects a wide variety of human cell lineages in vivo and in vitro, for long-term transgene expression without requirements for cell proliferation. The presented data demonstrate that recombinant AAV (rAAV) can efficiently transduce MOs as well as DCs generated by MO culture with granulocyte-macrophage colony-stimulating factor plus interleukin in vitro. rAAV transgene expression in MO-derived DCs could be enhanced by etoposide, previously reported to enhance AAV gene expression. rAAV transduction of freshly purified MO followed by 7 days of culture with cytokines to generate DCs, and subsequent sorting for coexpression of DC markers CD1a and CD40, showed robust transgene expression as well as evidence of nuclear localization of the rAAV genome in the DC population. Phenotypic analyses using multiple markers and functional assays of one-way allogeneic mixed leukocyte reactions indicated that rAAV-transduced MO-derived DCs were as equivalent to nontransduced DCs. These results support the utility of rAAV vectors for future human DC vaccine studies.

* Corresponding author. Mailing address: Department of Pathology, LHRB 513, 701 19th St. South, University of Alabama at Birmingham, Birmingham, AL 35294-0007. Phone: (205) 934-6731. Fax: (205) 975-9927. E-mail: sponnazh{at}path.uab.edu.

Journal of Virology, October 2001, p. 9493-9501, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9493-9501.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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