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Journal of Virology, September 2002, p. 9378-9388, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9378-9388.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vivo Gene Transfer Using a Nonprimate Lentiviral Vector Pseudotyped with Ross River Virus Glycoproteins

Yubin Kang,1 Colleen S. Stein,2 Jason A. Heth,2 Patrick L. Sinn,1 Andrea K. Penisten,1 Patrick D. Staber,2 Kenneth L. Ratliff,1 Hong Shen,1 Carrie K. Barker,1 Inês Martins,2 C. Matthew Sharkey,3 David Avram Sanders,3 Paul B. McCray, Jr.,1* and Beverly L. Davidson2,4,5*

Program in Gene Therapy, Department of Pediatrics,1 Department of Internal Medicine,2 Department of Neurology,5 Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242,4 Department of Biological Sciences, Purdue University, West Lafayette, Indiana 479073

Received 22 January 2002/ Accepted 18 March 2002

Vectors derived from lentiviruses provide a promising gene delivery system. We examined the in vivo gene transfer efficiency and tissue or cell tropism of a feline immunodeficiency virus (FIV)-based lentiviral vector pseudotyped with the glycoproteins from Ross River Virus (RRV). RRV glycoproteins were efficiently incorporated into FIV virions, generating preparations of FIV vector, which after concentration attain titers up to 1.5 x 108 TU/ml. After systemic administration, RRV-pseudotyped FIV vectors (RRV/FIV) predominantly transduced the liver of recipient mice. Transduction efficiency in the liver with the RRV/FIV was ca. 20-fold higher than that achieved with the vesicular stomatitis virus G protein (VSV-G) pseudotype. Moreover, in comparison to VSV-G, the RRV glycoproteins caused less cytotoxicity, as determined from the levels of glutamic pyruvic transaminase and glutamic oxalacetic transaminase in serum. Although hepatocytes were the main liver cell type transduced, nonhepatocytes (mainly Kupffer cells) were also transduced. The percentages of the transduced nonhepatocytes were comparable between RRV and VSV-G pseudotypes and did not correlate with the production of antibody against the transgene product. After injection into brain, RRV/FIV preferentially transduced neuroglial cells (astrocytes and oligodendrocytes). In contrast to the VSV-G protein that targets predominantly neurons, <10% of the brain cells transduced with the RRV pseudotyped vector were neurons. Finally, the gene transfer efficiencies of RRV/FIV after direct application to skeletal muscle or airway were also examined and, although transgene-expressing cells were detected, their proportions were low. Our data support the utility of RRV glycoprotein-pseudotyped FIV lentiviral vectors for hepatocyte- and neuroglia-related disease applications.

* Corresponding author. Mailing address for Beverly L. Davidson: Department of Internal Medicine, 200 EMRB, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 353-5511. Fax: (319) 353-5572. E-mail: beverly-davidson{at}uiowa.edu. Mailing address for Paul B. McCray, Jr.: Department of Pediatrics, 240 EMRB, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 356-4866. Fax: (319) 353-7171. E-mail: paul-mccray{at}iowa.edu.

Journal of Virology, September 2002, p. 9378-9388, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9378-9388.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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