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Journal of Virology, January 2000, p. 992-996, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Impaired Intracellular Trafficking of Adeno-Associated Virus Type 2 Vectors Limits Efficient Transduction of Murine Fibroblasts

Jonathan Hansen,1,2,3 Keyun Qing,1,2,3 Hyung-Joo Kwon,1,2,3 Cathryn Mah,4 and Arun Srivastava1,2,3,5,*

Department of Microbiology and Immunology,1 Walther Oncology Center,2 and Division of Hematology/Oncology, Department of Medicine,5 Indiana University School of Medicine, and Walther Cancer Institute,3 Indianapolis, Indiana 46202, and Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 326104

Received 9 September 1999/Accepted 18 October 1999

Although adeno-associated virus type 2 (AAV) has gained attention as a potentially useful alternative to the more commonly used retrovirus- and adenovirus-based vectors for human gene therapy, efficient gene transfer and transgene expression by AAV vectors require that the following two obstacles be overcome. First, the target cell must express the receptor and the coreceptor for AAV infection, and second, the cell must allow for viral second-strand DNA synthesis. We now describe a third obstacle, impaired intracellular trafficking of AAV to the nucleus, which results in the lack of transgene expression in murine fibroblasts which do express the AAV receptor and the coreceptor and which are permissive for viral second-strand DNA synthesis. We document that AAV vectors bind efficiently and gain entry successfully into NIH 3T3 cells, but trafficking into the nucleus is significantly impaired in these cells. In contrast, viral trafficking to the nucleus in cells known to be efficiently transduced by AAV vectors is both rapid and efficient. The demonstration of yet another obstacle in AAV-mediated gene transfer has implications for the optimal use of these vectors in human gene therapy.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Dr., Medical Science Building, Room 257, Indianapolis, IN 46202-5120. Phone: (317) 274-2194. Fax: (317) 274-4090. E-mail: asrivast{at}iupui.edu.

Journal of Virology, January 2000, p. 992-996, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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