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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 401-410
Efficient Gene Delivery to Quiescent Interleukin-2 (IL-2)-Dependent
Cells by Murine Leukemia Virus-Derived Vectors Harboring IL-2 Chimeric
Envelopes Glycoproteins
Marielle Maurice,
Stéphane Mazur,
Frances J. Bullough,
Anna Salvetti,
Mary K.L. Collins,
Stephen J. Russell, and
François-Loïc Cosset
From the Laboratoire de Vectorologie Rétrovirale et
Thérapie Génique, Unité de Virologie Humaine, INSERM
U412, Ecole Normale Supérieure de Lyon, Lyon, France; the Centre
de Génétique Moléculaire et Cellulaire, CNRS UMR5534,
Université Claude-Bernard Lyon-1, Villeurbanne, France; the
Cambridge Centre for Protein Engineering, MRC Centre, Cambridge, UK;
the Laboratoire de Thérapie Génique, CHU Hotel-Dieu,
Nantes, France; the Department of Immunology, Windeyer Institute for
Medical Science, University College London, London, UK; and Molecular
Medicine Program, Guggenheim 18, Mayo Clinic, Rochester, MN.
Interleukin-2 (IL-2) is a cytokine that induces the proliferation of
certain IL-2 receptor expressing quiescent cells. Human IL-2 was fused
to the amino-terminus of amphotropic murine leukemia virus (MLV)
envelope glycoproteins. Retroviral vectors were pseudotyped with both
the IL-2 chimeric envelope and the wild-type amphotropic MLV envelope.
The chimeric IL-2 glycoproteins were incorporated on retroviral vectors
and the IL-2-displaying vector particles could bind specifically to
cell surface IL-2 receptors. In addition, the IL-2-displaying vectors
could infect proliferating cells through amphotropic receptors
irrespective of whether the cells expressed the IL-2 receptor.
IL-2-displaying vector particles could also transiently stimulate the
cell cycle entry and proliferation of several IL-2-dependent cell
lines. Finally, retroviral vectors displaying IL-2 could efficiently
transduce G0/G1-arrested cells expressing the IL-2 receptor at a
34-fold higher efficiency compared with vectors with unmodified
envelopes. This new strategy, whereby C-type retroviral vector
particles display a ligand that activates the cell cycle of the target
cells at the time of virus entry, may represent an alternative to
lentivirus-derived retroviral vectors for the infection of quiescent
cells. In addition, upon infection of an heterogeneous population of
nonproliferating cells, MLV-retroviral vectors that display
cytokines/growth factors will allow the transgene of interest to be
integrated specifically in quiescent cells expressing the corresponding
cytokine/growth factor receptor.
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