Clinical application of lentiviral vector (LV)-based hematopoietic\nstem and progenitor cells (HSPC) gene therapy is rapidly becoming\na reality. Nevertheless, LV-mediated signaling and its potential\nfunctional consequences on HSPC biology remain poorly understood.\nWe unravel here a remarkably limited impact of LV on the\nHSPC transcriptional landscape. LV escaped innate immune sensing\nthat instead led to robust IFN responses upon transduction with a\ngamma-retroviral vector. However, reverse-transcribed LV DNA did\ntrigger p53 signaling, activated also by non-integrating Adenoassociated\nvector, ultimately leading to lower cell recovery ex vivo\nand engraftment in vivo. These effects were more pronounced in\nthe short-term repopulating cells while long-term HSC frequencies\nremained unaffected. Blocking LV-induced signaling partially\nrescued both apoptosis and engraftment, highlighting a novel\nstrategy to further dampen the impact of ex vivo gene transfer on\nHSPC. Overall, our results shed light on viral vector sensing in HSPC\nand provide critical insight for the development of more stealth\ngene therapy strategies.
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