Title: Lentiviral vector gene transfer is limited by the proteasome at postentry steps in various types of stem cells
Authors: Santoni de Sio, Francesca Romana ×
Gritti, Angela
Cascio, Paolo
Neri, Margherita
Sampaolesi, Maurilio
Galli, Cesare
Luban, Jeremy
Naldini, Luigi #
Issue Date: Aug-2008
Publisher: AlphaMed Press
Series Title: Stem Cells vol:26 issue:8 pages:2142-2152
Abstract: The isolation of human embryonic and somatic stem cells of different types has made it possible to design novel gene and cell replacement therapies. Vectors derived from retro/lentiviruses are used to stably introduce genes into stem cells and their progeny. However, the permissivity to retroviral infection varies among cell types. We previously showed that hematopoietic stem cells are poorly permissive to human immunodeficiency virus (HIV)-derived vectors and that pharmacological inhibition of the proteasome strongly enhances gene transfer. Here we report that the proteasome limits lentiviral gene transfer in all stem cell types tested, including embryonic, mesenchymal, and neural, of both human and mouse origin. Remarkably, this inhibitory activity was sharply reduced upon differentiation of the stem cells, suggesting that it represents a novel feature of the stem cell/immature progenitor phenotype. Proteasome-mediated inhibition was specific for lentiviral vectors and occurred at a postentry infection step. It was not mediated by activation of nuclear factor-kappa B, a major signaling pathway modulated by the proteasome, and did not correlate with high proteasome activity. Interaction of the virion core with cyclophilin A was required to maximize the effect of proteasome inhibitor on the infection pathway. These findings are relevant to uncover new mediators of HIV gene transfer and help in designing more effective protocols for the genetic modification of stem cells.
ISSN: 1066-5099
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Interdepartemental Stem Cell Institute (-)
× corresponding author
# (joint) last author

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