Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells

F Piras, M Riba, Carolina Petrillo, D Lazarevic, I Cuccovillo, S Bartolaccini, E Stupka, B Gentner, D Cittaro, L Naldini, A Kajaste-Rudnitski

Research output: Contribution to journalArticle

Abstract

Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape. LV escaped innate immune sensing that instead led to robust IFN responses upon transduction with a gamma-retroviral vector. However, reverse-transcribed LV DNA did trigger p53 signaling, activated also by non-integrating Adeno-associated vector, ultimately leading to lower cell recovery ex vivo and engraftment in vivo. These effects were more pronounced in the short-term repopulating cells while long-term HSC frequencies remained unaffected. Blocking LV-induced signaling partially rescued both apoptosis and engraftment, highlighting a novel strategy to further dampen the impact of ex vivo gene transfer on HSPC. Overall, our results shed light on viral vector sensing in HSPC and provide critical insight for the development of more stealth gene therapy strategies. © 2017 EMBO.
Original languageEnglish
Pages (from-to)1198-1211
Number of pages14
JournalEMBO Molecular Medicine
Volume9
Issue number1-2
Publication statusPublished - 2017

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Hematopoietic Stem Cells
Genetic Therapy
Cell- and Tissue-Based Therapy
Cell Biology
Apoptosis
DNA

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Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells. / Piras, F; Riba, M; Petrillo, Carolina; Lazarevic, D; Cuccovillo, I; Bartolaccini, S; Stupka, E; Gentner, B; Cittaro, D; Naldini, L; Kajaste-Rudnitski, A.

In: EMBO Molecular Medicine, Vol. 9, No. 1-2, 2017, p. 1198-1211.

Research output: Contribution to journalArticle

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abstract = "Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape. LV escaped innate immune sensing that instead led to robust IFN responses upon transduction with a gamma-retroviral vector. However, reverse-transcribed LV DNA did trigger p53 signaling, activated also by non-integrating Adeno-associated vector, ultimately leading to lower cell recovery ex vivo and engraftment in vivo. These effects were more pronounced in the short-term repopulating cells while long-term HSC frequencies remained unaffected. Blocking LV-induced signaling partially rescued both apoptosis and engraftment, highlighting a novel strategy to further dampen the impact of ex vivo gene transfer on HSPC. Overall, our results shed light on viral vector sensing in HSPC and provide critical insight for the development of more stealth gene therapy strategies. {\circledC} 2017 EMBO.",
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AU - Piras, F

AU - Riba, M

AU - Petrillo, Carolina

AU - Lazarevic, D

AU - Cuccovillo, I

AU - Bartolaccini, S

AU - Stupka, E

AU - Gentner, B

AU - Cittaro, D

AU - Naldini, L

AU - Kajaste-Rudnitski, A

PY - 2017

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AB - Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape. LV escaped innate immune sensing that instead led to robust IFN responses upon transduction with a gamma-retroviral vector. However, reverse-transcribed LV DNA did trigger p53 signaling, activated also by non-integrating Adeno-associated vector, ultimately leading to lower cell recovery ex vivo and engraftment in vivo. These effects were more pronounced in the short-term repopulating cells while long-term HSC frequencies remained unaffected. Blocking LV-induced signaling partially rescued both apoptosis and engraftment, highlighting a novel strategy to further dampen the impact of ex vivo gene transfer on HSPC. Overall, our results shed light on viral vector sensing in HSPC and provide critical insight for the development of more stealth gene therapy strategies. © 2017 EMBO.

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