Targeted cell entry of lentiviral vectors

Sabrina Funke, Andrea Maisner, Michael D. Mühlebach, Ulrike Koehl, Manuel Grez, Roberto Cattaneo, Klaus Cichutek, Christian J. Buchholz

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

Retargeting of lentiviral vector entry to cell types of interest is a key factor in improving the safety and efficacy of gene transfer. In this study we show that the retargetable envelope glycoproteins of measles virus (MV), namely, the hemagglutinin (H) responsible for receptor recognition and the fusion protein (F), can pseudotype human immunodeficiency virus 1 (HIV-1) vectors when their cytoplasmic tails are truncated. We then pseudotyped HIV-1 vectors with MV glycoproteins displaying on H either the epidermal growth factor or a single-chain antibody directed against CD20, but without the ability to recognize their native receptors. Gene transfer into cells that expressed the targeted receptor was several orders of magnitude more efficient than into cells that did not. High-target versus nontarget cell discrimination was demonstrated in mixed cell populations, where the targeting vector selectively eliminated CD20-positive cells after suicide gene transfer. Remarkably, primary human CD20-positive B lymphocytes were transduced more efficiently by the CD20-targeted vector than by a vector pseudotyped with the vesicular stomatitis virus G (VSV-G) protein. In addition, the CD20-targeted vector was able to transduce even unstimulated primary B cells, whereas VSV-G pseudotyped vectors were unable to do so. Because MV enters cells through direct fusion at the cell membrane, this novel targeting system should be widely applicable.

Original languageEnglish (US)
Pages (from-to)1427-1436
Number of pages10
JournalMolecular Therapy
Volume16
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

Measles virus
HIV-1
Glycoproteins
B-Lymphocytes
Genes
Single-Chain Antibodies
Vesicular Stomatitis
Aptitude
Hemagglutinins
Epidermal Growth Factor
Suicide
Tail
Cell Membrane
Viruses
Safety
Population
Proteins

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Funke, S., Maisner, A., Mühlebach, M. D., Koehl, U., Grez, M., Cattaneo, R., ... Buchholz, C. J. (2008). Targeted cell entry of lentiviral vectors. Molecular Therapy, 16(8), 1427-1436. https://doi.org/10.1038/mt.2008.128

Targeted cell entry of lentiviral vectors. / Funke, Sabrina; Maisner, Andrea; Mühlebach, Michael D.; Koehl, Ulrike; Grez, Manuel; Cattaneo, Roberto; Cichutek, Klaus; Buchholz, Christian J.

In: Molecular Therapy, Vol. 16, No. 8, 08.2008, p. 1427-1436.

Research output: Contribution to journalArticle

Funke, S, Maisner, A, Mühlebach, MD, Koehl, U, Grez, M, Cattaneo, R, Cichutek, K & Buchholz, CJ 2008, 'Targeted cell entry of lentiviral vectors', Molecular Therapy, vol. 16, no. 8, pp. 1427-1436. https://doi.org/10.1038/mt.2008.128
Funke S, Maisner A, Mühlebach MD, Koehl U, Grez M, Cattaneo R et al. Targeted cell entry of lentiviral vectors. Molecular Therapy. 2008 Aug;16(8):1427-1436. https://doi.org/10.1038/mt.2008.128
Funke, Sabrina ; Maisner, Andrea ; Mühlebach, Michael D. ; Koehl, Ulrike ; Grez, Manuel ; Cattaneo, Roberto ; Cichutek, Klaus ; Buchholz, Christian J. / Targeted cell entry of lentiviral vectors. In: Molecular Therapy. 2008 ; Vol. 16, No. 8. pp. 1427-1436.
@article{d1f468d4d523475a8c45b7c2203d55e1,
title = "Targeted cell entry of lentiviral vectors",
abstract = "Retargeting of lentiviral vector entry to cell types of interest is a key factor in improving the safety and efficacy of gene transfer. In this study we show that the retargetable envelope glycoproteins of measles virus (MV), namely, the hemagglutinin (H) responsible for receptor recognition and the fusion protein (F), can pseudotype human immunodeficiency virus 1 (HIV-1) vectors when their cytoplasmic tails are truncated. We then pseudotyped HIV-1 vectors with MV glycoproteins displaying on H either the epidermal growth factor or a single-chain antibody directed against CD20, but without the ability to recognize their native receptors. Gene transfer into cells that expressed the targeted receptor was several orders of magnitude more efficient than into cells that did not. High-target versus nontarget cell discrimination was demonstrated in mixed cell populations, where the targeting vector selectively eliminated CD20-positive cells after suicide gene transfer. Remarkably, primary human CD20-positive B lymphocytes were transduced more efficiently by the CD20-targeted vector than by a vector pseudotyped with the vesicular stomatitis virus G (VSV-G) protein. In addition, the CD20-targeted vector was able to transduce even unstimulated primary B cells, whereas VSV-G pseudotyped vectors were unable to do so. Because MV enters cells through direct fusion at the cell membrane, this novel targeting system should be widely applicable.",
author = "Sabrina Funke and Andrea Maisner and M{\"u}hlebach, {Michael D.} and Ulrike Koehl and Manuel Grez and Roberto Cattaneo and Klaus Cichutek and Buchholz, {Christian J.}",
year = "2008",
month = "8",
doi = "10.1038/mt.2008.128",
language = "English (US)",
volume = "16",
pages = "1427--1436",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Targeted cell entry of lentiviral vectors

AU - Funke, Sabrina

AU - Maisner, Andrea

AU - Mühlebach, Michael D.

AU - Koehl, Ulrike

AU - Grez, Manuel

AU - Cattaneo, Roberto

AU - Cichutek, Klaus

AU - Buchholz, Christian J.

PY - 2008/8

Y1 - 2008/8

N2 - Retargeting of lentiviral vector entry to cell types of interest is a key factor in improving the safety and efficacy of gene transfer. In this study we show that the retargetable envelope glycoproteins of measles virus (MV), namely, the hemagglutinin (H) responsible for receptor recognition and the fusion protein (F), can pseudotype human immunodeficiency virus 1 (HIV-1) vectors when their cytoplasmic tails are truncated. We then pseudotyped HIV-1 vectors with MV glycoproteins displaying on H either the epidermal growth factor or a single-chain antibody directed against CD20, but without the ability to recognize their native receptors. Gene transfer into cells that expressed the targeted receptor was several orders of magnitude more efficient than into cells that did not. High-target versus nontarget cell discrimination was demonstrated in mixed cell populations, where the targeting vector selectively eliminated CD20-positive cells after suicide gene transfer. Remarkably, primary human CD20-positive B lymphocytes were transduced more efficiently by the CD20-targeted vector than by a vector pseudotyped with the vesicular stomatitis virus G (VSV-G) protein. In addition, the CD20-targeted vector was able to transduce even unstimulated primary B cells, whereas VSV-G pseudotyped vectors were unable to do so. Because MV enters cells through direct fusion at the cell membrane, this novel targeting system should be widely applicable.

AB - Retargeting of lentiviral vector entry to cell types of interest is a key factor in improving the safety and efficacy of gene transfer. In this study we show that the retargetable envelope glycoproteins of measles virus (MV), namely, the hemagglutinin (H) responsible for receptor recognition and the fusion protein (F), can pseudotype human immunodeficiency virus 1 (HIV-1) vectors when their cytoplasmic tails are truncated. We then pseudotyped HIV-1 vectors with MV glycoproteins displaying on H either the epidermal growth factor or a single-chain antibody directed against CD20, but without the ability to recognize their native receptors. Gene transfer into cells that expressed the targeted receptor was several orders of magnitude more efficient than into cells that did not. High-target versus nontarget cell discrimination was demonstrated in mixed cell populations, where the targeting vector selectively eliminated CD20-positive cells after suicide gene transfer. Remarkably, primary human CD20-positive B lymphocytes were transduced more efficiently by the CD20-targeted vector than by a vector pseudotyped with the vesicular stomatitis virus G (VSV-G) protein. In addition, the CD20-targeted vector was able to transduce even unstimulated primary B cells, whereas VSV-G pseudotyped vectors were unable to do so. Because MV enters cells through direct fusion at the cell membrane, this novel targeting system should be widely applicable.

UR - http://www.scopus.com/inward/record.url?scp=48349147731&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48349147731&partnerID=8YFLogxK

U2 - 10.1038/mt.2008.128

DO - 10.1038/mt.2008.128

M3 - Article

C2 - 18578012

AN - SCOPUS:48349147731

VL - 16

SP - 1427

EP - 1436

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 8

ER -