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Transient proteasome inhibition as a strategy to enhance lentiviral transduction of hematopoietic CD34 + cells and T lymphocytes: Implications for the use of low viral doses and large-size vectors

Transient proteasome inhibition as a strategy to enhance lentiviral transduction of hematopoietic CD34 + cells and T lymphocytes: Implications for the

Transient proteasome inhibition as a strategy to enhance lentiviral transduction of hematopoietic CD34 + cells and T lymphocytes: Implications for the use of low viral doses and large-size vectors  
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Valeria Leuci, Giulia Mesiano, Loretta Gammaitoni, Cristina Cammarata, Sonia Capellero, Maja Todorovic, Noela Jordaney, Paola Circosta, Angela Elia, Marina Lesnikova, George E. Georges, Wanda Piacibellohttp://academic.research.microsoft.com/io.ashx?type=5&id=49222899&selfId1=0&selfId2=0&maxNumber=12&query=
The proteasome system restricts lentiviral transduction of stem cells. We exploited proteasome inhibition as a strategy to enhance transduction of both hematopoietic stem cells (HSC) and T lymphocytes with low dose or large-size lentiviral vectors (LV). HSC showed higher transduction efficiency if transiently exposed to proteasome inhibitor MG132 (41.8% vs 10.7%, p<0.0001). Treatment with MG132 (0.5μM) retained its beneficial effect with 3 different LV of increasing size up to 10.9Kb (p<0.01). We extended, for the first time, the application of proteasome inhibition to the transduction of T lymphocytes. A transient exposure to MG132 significantly improved lentiviral T-cell transduction. The mean percentage of transduced T cells progressively increased from 13.5% of untreated cells, to 21% (p=0.3), 30% (p=0.03) and 37% (p=0.01) of T lymphocytes that were pre-treated with MG132 at 0.1, 0.5 and 1μM, respectively. MG132 did not affect viability or functionality of HSC or T cells, nor significantly increased the number of integrated vector copies. Transient proteasome inhibition appears as a new procedure to safely enhance lentiviral transduction of HSC and T lymphocytes with low viral doses. This approach could be useful in settings where the use of large size vectors may impair optimal viral production.
Journal: Journal of Biotechnology - J BIOTECHNOL , vol. 156, no. 3, pp. 218-226, 2011
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