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Journal of Virology, August 2009, p. 8153-8162, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00220-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The CXCR4-Tropic Human Immunodeficiency Virus Envelope Promotes More-Efficient Gene Delivery to Resting CD4+ T Cells than the Vesicular Stomatitis Virus Glycoprotein G Envelope{triangledown} ,{dagger}

Luis M. Agosto,1 Jianqing J. Yu,2 Megan K. Liszewski,3 Clifford Baytop,2 Nikolay Korokhov,4 Laurent M. Humeau,4 and Una O'Doherty2*

Department of Microbiology,1 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine,2 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104,3 VIRxSYS Corporation, Gaithersburg, Maryland 208774

Received 30 January 2009/ Accepted 29 May 2009

Current gene transfer protocols for resting CD4+ T cells include an activation step to enhance transduction efficiency. This step is performed because it is thought that resting cells are resistant to transduction by lentiviral-based gene therapy vectors. However, activating resting cells prior to transduction alters their physiology, with foreseeable and unforeseeable negative consequences. Thus, it would be desirable to transduce resting CD4+ T cells without activation. We recently demonstrated, contrary to the prevailing belief, that wild-type human immunodeficiency virus (HIV) integrates into resting CD4+ T cells. Based on that finding, we investigated whether a commonly used, vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped lentiviral gene therapy vector could also integrate into resting CD4+ T cells. To investigate this, we inoculated resting CD4+ T cells with lentiviral particles that were pseudotyped with VSV-G or CXCR4-tropic HIV Env and assayed binding, fusion, reverse transcription, and integration. We found that the VSV-G-pseudotyped lentiviral vector failed to fuse to resting CD4+ T cells while HIV Env-pseudotyped lentiviral vectors fused, reverse transcribed, and integrated in resting cells. Our findings suggest that HIV Env could be used effectively for the delivery of therapeutic genes to resting CD4+ T cells and suggest that fusion may be the critical step restricting transduction of resting CD4+ T cells by lentiviral gene therapy vectors.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Room 265, John Morgan Building, Philadelphia, PA 19104. Phone: (215) 573-7273. Fax: (215) 573-2348. E-mail: unao{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 3 June 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, August 2009, p. 8153-8162, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00220-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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