Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells
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 remarkabl...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201707922 |
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| _version_ | 1849761822837571584 |
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| author | Francesco Piras Michela Riba Carolina Petrillo Dejan Lazarevic Ivan Cuccovillo Sara Bartolaccini Elia Stupka Bernhard Gentner Davide Cittaro Luigi Naldini Anna Kajaste‐Rudnitski |
| author_facet | Francesco Piras Michela Riba Carolina Petrillo Dejan Lazarevic Ivan Cuccovillo Sara Bartolaccini Elia Stupka Bernhard Gentner Davide Cittaro Luigi Naldini Anna Kajaste‐Rudnitski |
| author_sort | Francesco Piras |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7e75a85b5c0347b0ba9cf82f60a719be |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-7e75a85b5c0347b0ba9cf82f60a719be2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-06-01991198121110.15252/emmm.201707922Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cellsFrancesco Piras0Michela Riba1Carolina Petrillo2Dejan Lazarevic3Ivan Cuccovillo4Sara Bartolaccini5Elia Stupka6Bernhard Gentner7Davide Cittaro8Luigi Naldini9Anna Kajaste‐Rudnitski10San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteCenter for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteCenter for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteCenter for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteCenter for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteAbstract 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.https://doi.org/10.15252/emmm.201707922gene therapyhematopoietic stem and progenitor cellsinnate sensinglentiviral vectorsp53 signaling |
| spellingShingle | Francesco Piras Michela Riba Carolina Petrillo Dejan Lazarevic Ivan Cuccovillo Sara Bartolaccini Elia Stupka Bernhard Gentner Davide Cittaro Luigi Naldini Anna Kajaste‐Rudnitski Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells EMBO Molecular Medicine gene therapy hematopoietic stem and progenitor cells innate sensing lentiviral vectors p53 signaling |
| title | Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells |
| title_full | Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells |
| title_fullStr | Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells |
| title_full_unstemmed | Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells |
| title_short | Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells |
| title_sort | lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells |
| topic | gene therapy hematopoietic stem and progenitor cells innate sensing lentiviral vectors p53 signaling |
| url | https://doi.org/10.15252/emmm.201707922 |
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