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Blood, 15 December 2008, Vol. 112, No. 13, pp. 4843-4852.
Prepublished online as a Blood First Edition Paper on September 23, 2008; DOI 10.1182/blood-2008-05-155945.
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Submitted May 14, 2008
Accepted September 1, 2008
Stable transduction of quiescent T-cells without induction of cycle progression by a novel lentiviral vector pseudotyped with measles virus glycoproteins
Cecilia Frecha, Caroline Costa, Didier Negre, Emmanuel Gauthier, Stephen J Russell, Francois-Loic Cosset*, and Els Verhoeyen
Universite de Lyon, Human Virology Department, Inserm U758 - ENS Lyon, Lyon, France
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
* Corresponding author; email: flcosset{at}ens-lyon.fr.
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 T-cells (11%) with H/F-LVs, which seemed to occur mainly through SLAM, was not at cost of cell cycle entry or of target T-cells 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.
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