Efficient gene delivery to quiescent interleukin-2 (IL-2)-dependent cells by murine leukemia virus-derived vectors harboring IL-2 chimeric envelope glycoproteins.
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.
Maurice
M
M
Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, Unité de Virologie Humaine, INSERM U412, Ecole Normale Supérieure de Lyon, Lyon, France.
Mazur
S
S
Bullough
F J
FJ
Salvetti
A
A
Collins
M K
MK
Russell
S J
SJ
Cosset
F L
FL
D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D004261:DNA Replication; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology*; D008979:Moloney murine leukemia virus / Q000235:genetics* / Q000502:physiology; D028061:Phosphate Transport Proteins; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D014162:Transfection / Q000379:methods*; D016662:Virus Integration
D007376:Interleukin-2; D028061:Phosphate Transport Proteins; D015375:Receptors, Interleukin-2; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters