Stable transduction of quiescent T cells without induction of cycle progression by a novel lentiviral vector pseudotyped with measles virus glycoproteins.
A major limitation of current lentiviral vectors (LVs) is their inability to govern efficient gene transfer into quiescent cells such as primary T cells, which hampers their application for gene therapy. Here we generated high-titer LVs incorporating Edmonston measles virus (MV) glycoproteins H and F on their surface. They allowed efficient transduction through the MV receptors, SLAM and CD46, both present on blood T cells. Indeed, these H/F-displaying vectors outperformed by far VSV-G-LVs for the transduction of IL-7-prestimulated T cells. More importantly, a single exposure to these H/F-LVs allowed efficient gene transfer in quiescent T cells, which are not permissive for VSV-G-LVs that need cell-cycle entry into the G1b phase for efficient transduction. High-level transduction of resting memory (50%) and naive (11%) T cells with H/F-LVs, which seemed to occur mainly through SLAM, was not at cost of cell-cycle entry or of target T-cell activation. Finally, the naive or memory phenotypes of transduced resting T cells were maintained and no changes in cytokine profiles were detected, suggesting that T-cell populations were not skewed. Thus, H/F-LV transduction of resting T cells overcomes the limitation of current lentiviral vectors and may improve the efficacy of T cell-based gene therapy.
Frecha
Cecilia
C
Université de Lyon, Inserm U758, Human Virology Department, Ecole Normale Supérieure de Lyon, Lyon, France.
Costa
Caroline
C
Nègre
Didier
D
Gauthier
Emmanuel
E
Russell
Stephen J
SJ
Cosset
François-Loïc
FL
Verhoeyen
Els
E
D002453:Cell Cycle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D007962:Leukocytes; D008459:Measles virus / Q000737:chemistry / Q000235:genetics*; D011991:Receptors, Virus / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods*; D014759:Viral Envelope Proteins / Q000235:genetics
D006023:Glycoproteins; D011991:Receptors, Virus; D014759:Viral Envelope Proteins