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

• DOI: 10.15252/emmm.201707922
• Publication Date: 2017-07-01T00:10:44Z
• Authors: Francesco Piras; Michela Riba; Carolina Petrillo; Dejan Lazarevic; Ivan Cuccovillo; Sara Bartolaccini; Elia Stupka; Bernhard Gentner; Davide Cittaro; Luigi Naldini; Anna Kajaste‐Rudn...
• Keywords: Transduction (biophysics); Ex vivo; Hematopoietic stem cell

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 its potential functional consequences on HSPC biology remain poorly understood. We unravel here remarkably limited impact LV the transcriptional landscape. escaped innate immune sensing that instead led to robust IFN responses upon transduction with gamma‐retroviral vector. However, reverse‐transcribed DNA did trigger p53 signaling, activated also by non‐integrating Adeno‐associated vector, ultimately leading lower cell recovery ex vivo engraftment in . These effects were more pronounced short‐term repopulating while long‐term HSC frequencies remained unaffected. Blocking LV‐induced partially rescued both apoptosis engraftment, highlighting novel strategy further dampen transfer HSPC. Overall, our results shed light viral provide critical insight for development stealth strategies.