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Journal of Virology, May 2003, p. 5902-5910, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5902-5910.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Lentivirus Vectors Pseudotyped with Filoviral Envelope Glycoproteins Transduce Airway Epithelia from the Apical Surface Independently of Folate Receptor Alpha

Patrick L. Sinn,1 Melissa A. Hickey,1 Patrick D. Staber,2 Douglas E. Dylla,1 Scott A. Jeffers,3 Beverly L. Davidson,2 David A. Sanders,3 and Paul B. McCray Jr.1*

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

Received 27 September 2002/ Accepted 19 February 2003

The practical application of gene therapy as a treatment for cystic fibrosis is limited by poor gene transfer efficiency with vectors applied to the apical surface of airway epithelia. Recently, folate receptor alpha (FR{alpha}), a glycosylphosphatidylinositol-linked surface protein, was reported to be a cellular receptor for the filoviruses. We found that polarized human airway epithelia expressed abundant FR{alpha} on their apical surface. In an attempt to target these apical receptors, we pseudotyped feline immunodeficiency virus (FIV)-based vectors by using envelope glycoproteins (GPs) from the filoviruses Marburg virus and Ebola virus. Importantly, primary cultures of well-differentiated human airway epithelia were transduced when filovirus GP-pseudotyped FIV was applied to the apical surface. Furthermore, by deleting a heavily O-glycosylated extracellular domain of the Ebola GP, we improved the titer of concentrated vector severalfold. To investigate the folate receptor dependence of gene transfer with the filovirus pseudotypes, we compared gene transfer efficiency in immortalized airway epithelium cell lines and primary cultures. By utilizing phosphatidylinositol-specific phospholipase C (PI-PLC) treatment and FR{alpha}-blocking antibodies, we demonstrated FR{alpha}-dependent and -independent entry by filovirus glycoprotein-pseudotyped FIV-based vectors in airway epithelia. Of particular interest, entry independent of FR{alpha} was observed in primary cultures of human airway epithelia. Understanding viral vector binding and entry pathways is fundamental for developing cystic fibrosis gene therapy applications.

* Corresponding author. Mailing address: Department of Pediatrics, 240 EMRB, The University of Iowa, Iowa City, IA 52242. Phone: (319) 356-4866. Fax: (319) 356-7171. E-mail: paul-mccray{at}uiowa.edu.

Journal of Virology, May 2003, p. 5902-5910, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5902-5910.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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