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Journal of Virology, February 2002, p. 1135-1143, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1135-1143.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A High-Capacity, Capsid-Modified Hybrid Adenovirus/Adeno-Associated Virus Vector for Stable Transduction of Human Hematopoietic Cells

Dmitry M. Shayakhmetov, Cheryl A. Carlson, Hartmut Stecher, Qiliang Li, George Stamatoyannopoulos, and André Lieber*

Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195

Received 16 July 2001/ Accepted 25 October 2001

To achieve stable gene transfer into human hematopoietic cells, we constructed a new vector, {Delta}Ad5/35.AAV. This vector has a chimeric capsid containing adenovirus type 35 fibers, which conferred efficient infection of human hematopoietic cells. The {Delta}Ad5/35.AAV vector genome is deleted for all viral genes, allowing for infection without virus-associated toxicity. To generate high-capacity {Delta}Ad5/35.AAV vectors, we employed a new technique based on recombination between two first-generation adenovirus vectors. The resultant vector genome contained an 11.6-kb expression cassette including the human {gamma}-globin gene and the HS2 and HS3 elements of the ß-globin locus control region. The expression cassette was flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs). Infection with {Delta}Ad5/35.AAV allowed for stable transgene expression in a hematopoietic cell line after integration into the host genome through the AAV ITR(s). This new vector exhibits advantages over existing integrating vectors, including an increased insert capacity and tropism for hematopoietic cells. It has the potential for stable ex vivo transduction of hematopoietic stem cells in order to treat sickle cell disease.

* Corresponding author. Mailing address: University of Washington, Division of Medical Genetics, Box 357720, 1705 NE Pacific St., Seattle, WA 98195. Phone: (206) 221-3973. Fax: (206) 685-8675. E-mail: lieber00{at}u.washington.edu.

Journal of Virology, February 2002, p. 1135-1143, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1135-1143.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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