A hyperfusogenic gibbon ape leukemia envelope glycoprotein: Targeting of a cytotoxic gene by ligand display

Adele K. Fielding, Sylvie Chapel-Fernandes, Mark P. Chadwick, Frances J. Bullough, François Loïc Cosset, Stephen J. Russell

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

An important goal in cancer gene therapy is the development of novel targeted cytotoxic genes. The observation that transfection of a GaLV envelope glycoprotein lacking an R peptide into human cells results in considerable cell-cell fusion and subsequent cell death prompted us to explore the potential for using this fusogenic membrane glycoprotein (FMG) as a targeted cytotoxic gene. As proof of principle, we therefore displayed epidermal growth factor (EGF) on the N terminus of GaLV envelope glycoproteins both with and without an R peptide (GaLV R+ and GaLV R-). Transfection of the GaLVR+ envelope expression plasmids did not cause cell- cell fusion. The GaLV R+ envelopes were incorporated into retroviral vectors whose infectivity was investigated on EGF receptor-positive and -negative cells. The vector incorporating an N-terminally unmodified envelope was able to infect all human cell lines tested. Infectivity of the vector incorporating an envelope on which EGF was displayed was restricted on EGF receptor-positive cells (but not on EGF receptor-negative cells) and could be restored by protease cleavage of the displayed domain or competition with exogenous ligand. The cell-cell fusion capacity of the GaLV R- envelope glycoproteins (N-terminally unmodified and with N-terminal display of both EGF and insulin-like growth factor I [IGF-I]) was investigated by plasmid DNA transfection. While the N-terminally unmodified GaLV R- fused all human cell types tested, fusogenicity of GaLV R- on which EGF or IGF-I was displayed was considerably restricted on receptor-positive cells. 'Reciprocal' competition experiments showed that fusogenicity could be restored by competition only with the relevant exogenous ligand. Thus the specificity of cell-cell fusion by a hyperfusogenic GaLV envelope glycoprotein can be regulated by N-terminal display of growth factor ligands. There is therefore significant potential for further development of the targeting of the cell-killing capability of tiffs fusogenic viral glycoprotein by using strategies similar to those we have developed for the targeting of retroviral vectors.

Original languageEnglish (US)
Pages (from-to)817-826
Number of pages10
JournalHuman gene therapy
Volume11
Issue number6
DOIs
StatePublished - Apr 10 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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