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  1. Article ; Online: Interferon-inducible phospholipids govern IFITM3-dependent endosomal antiviral immunity.

    Unali, Giulia / Crivicich, Giovanni / Pagani, Isabel / Abou-Alezz, Monah / Folchini, Filippo / Valeri, Erika / Matafora, Vittoria / Reisz, Julie A / Giordano, Anna Maria Sole / Cuccovillo, Ivan / Butta, Giacomo M / Donnici, Lorena / D'Alessandro, Angelo / De Francesco, Raffaele / Manganaro, Lara / Cittaro, Davide / Merelli, Ivan / Petrillo, Carolina / Bachi, Angela /
    Vicenzi, Elisa / Kajaste-Rudnitski, Anna

    The EMBO journal

    2023  Volume 42, Issue 10, Page(s) e112234

    Abstract: The interferon-induced transmembrane proteins (IFITM) are implicated in several biological processes, including antiviral defense, but their modes of action remain debated. Here, taking advantage of pseudotyped viral entry assays and replicating viruses, ...

    Abstract The interferon-induced transmembrane proteins (IFITM) are implicated in several biological processes, including antiviral defense, but their modes of action remain debated. Here, taking advantage of pseudotyped viral entry assays and replicating viruses, we uncover the requirement of host co-factors for endosomal antiviral inhibition through high-throughput proteomics and lipidomics in cellular models of IFITM restriction. Unlike plasma membrane (PM)-localized IFITM restriction that targets infectious SARS-CoV2 and other PM-fusing viral envelopes, inhibition of endosomal viral entry depends on lysines within the conserved IFITM intracellular loop. These residues recruit Phosphatidylinositol 3,4,5-trisphosphate (PIP3) that we show here to be required for endosomal IFITM activity. We identify PIP3 as an interferon-inducible phospholipid that acts as a rheostat for endosomal antiviral immunity. PIP3 levels correlated with the potency of endosomal IFITM restriction and exogenous PIP3 enhanced inhibition of endocytic viruses, including the recent SARS-CoV2 Omicron variant. Together, our results identify PIP3 as a critical regulator of endosomal IFITM restriction linking it to the Pi3K/Akt/mTORC pathway and elucidate cell-compartment-specific antiviral mechanisms with potential relevance for the development of broadly acting antiviral strategies.
    MeSH term(s) Humans ; Antiviral Agents ; Interferons/metabolism ; Phospholipids ; Phosphatidylinositol 3-Kinases/metabolism ; RNA, Viral ; RNA-Binding Proteins/metabolism ; COVID-19 ; SARS-CoV-2/metabolism ; Virus Internalization ; Membrane Proteins/metabolism
    Chemical Substances Antiviral Agents ; Interferons (9008-11-1) ; Phospholipids ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; RNA, Viral ; RNA-Binding Proteins ; Membrane Proteins ; IFITM3 protein, human
    Language English
    Publishing date 2023-03-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2022112234
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1808: Show issues Location:
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  2. Article ; Online: Assessing the Impact of Cyclosporin A on Lentiviral Transduction and Preservation of Human Hematopoietic Stem Cells in Clinically Relevant

    Petrillo, Carolina / Calabria, Andrea / Piras, Francesco / Capotondo, Alessia / Spinozzi, Giulio / Cuccovillo, Ivan / Benedicenti, Fabrizio / Naldini, Luigi / Montini, Eugenio / Biffi, Alessandra / Gentner, Bernhard / Kajaste-Rudnitski, Anna

    Human gene therapy

    2019  Volume 30, Issue 9, Page(s) 1133–1146

    Abstract: Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to lentiviral vector (LV) transduction without compromising their biological properties remains critical for broad-range implementation of gene therapy as a treatment option for ... ...

    Abstract Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to lentiviral vector (LV) transduction without compromising their biological properties remains critical for broad-range implementation of gene therapy as a treatment option for several inherited diseases. This study demonstrates that the use of one-hit
    MeSH term(s) Animals ; Cell Cycle/drug effects ; Cell Cycle/genetics ; Cell Proliferation/drug effects ; Chromosome Mapping ; Colony-Forming Units Assay ; Cyclosporine/pharmacology ; Gene Transfer Techniques ; Genetic Therapy/methods ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Graft Survival/drug effects ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Lentivirus/genetics ; Mice ; Mice, Knockout ; Transduction, Genetic ; Virus Integration
    Chemical Substances Cyclosporine (83HN0GTJ6D)
    Language English
    Publishing date 2019-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1028152-6
    ISSN 1557-7422 ; 1043-0342
    ISSN (online) 1557-7422
    ISSN 1043-0342
    DOI 10.1089/hum.2019.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2988: Show issues Location:
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  3. Article ; Online: Cyclosporin a and rapamycin relieve distinct lentiviral restriction blocks in hematopoietic stem and progenitor cells.

    Petrillo, Carolina / Cesana, Daniela / Piras, Francesco / Bartolaccini, Sara / Naldini, Luigi / Montini, Eugenio / Kajaste-Rudnitski, Anna

    Molecular therapy : the journal of the American Society of Gene Therapy

    2014  Volume 23, Issue 2, Page(s) 352–362

    Abstract: Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to HIV-derived lentiviral vectors (LVs) remains a challenge for the field of gene therapy as high vector doses and prolonged ex vivo culture are still required to achieve clinically ... ...

    Abstract Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to HIV-derived lentiviral vectors (LVs) remains a challenge for the field of gene therapy as high vector doses and prolonged ex vivo culture are still required to achieve clinically relevant transduction levels. We report here that Cyclosporin A (CsA) and Rapamycin (Rapa) significantly improve LV gene transfer in human and murine HSPC. Both compounds increased LV but not gammaretroviral transduction and acted independently of calcineurin and autophagy. Improved gene transfer was achieved across all CD34(+) subpopulations, including in long-term SCID repopulating cells. Effects of CsA were specific of HSPC and opposite to its known impact on HIV replication. Mutating the Cyclophilin A binding pocket of the viral capsid (CA) further improved transduction in combination with CsA. Tracking of the LV genome fate revealed that CsA relieves a CA-dependent early block and increases integration, while Rapa acts early in LV infection independently of the viral CA. In agreement, only Rapa was able to improve transduction by an integrase-defective LV harboring wild-type CA. Overall, our findings pave the way for more efficient and sustainable LV gene therapy in human HSPCs and shed light on the multiple innate barriers specifically hampering LV transduction in these cells.
    MeSH term(s) Animals ; Cell Differentiation ; Cyclosporine/pharmacology ; Fetal Blood/cytology ; Gene Expression ; Genetic Vectors/genetics ; Graft Survival ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Immunophenotyping ; Lentivirus/genetics ; Mice ; Phenotype ; Sirolimus/pharmacology ; Transduction, Genetic ; Transgenes
    Chemical Substances Cyclosporine (83HN0GTJ6D) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2014-10-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1038/mt.2014.193
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5640: Show issues Location:
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  4. Article ; Online: Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells.

    Piras, Francesco / Riba, Michela / Petrillo, Carolina / Lazarevic, Dejan / Cuccovillo, Ivan / Bartolaccini, Sara / Stupka, Elia / Gentner, Bernhard / Cittaro, Davide / Naldini, Luigi / Kajaste-Rudnitski, Anna

    EMBO molecular medicine

    2017  Volume 9, Issue 9, Page(s) 1198–1211

    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 ... ...

    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
    MeSH term(s) Animals ; Genetic Therapy ; Genetic Vectors/genetics ; Genetic Vectors/immunology ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/immunology ; Humans ; Immunity, Innate ; Lentivirus/genetics ; Lentivirus/immunology ; Mice ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/immunology
    Chemical Substances Tumor Suppressor Protein p53
    Language English
    Publishing date 2017-06-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.201707922
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6784: Show issues Location:
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  5. Article ; Online: Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy.

    Zonari, Erika / Desantis, Giacomo / Petrillo, Carolina / Boccalatte, Francesco E / Lidonnici, Maria Rosa / Kajaste-Rudnitski, Anna / Aiuti, Alessandro / Ferrari, Giuliana / Naldini, Luigi / Gentner, Bernhard

    Stem cell reports

    2017  Volume 8, Issue 4, Page(s) 977–990

    Abstract: Ex vivo gene therapy based on ... ...

    Abstract Ex vivo gene therapy based on CD34
    MeSH term(s) ADP-ribosyl Cyclase 1/analysis ; Animals ; Antigens, CD34/analysis ; Cell Culture Techniques ; Cell Engineering/methods ; Cell Proliferation ; Genetic Therapy/methods ; Genetic Vectors/genetics ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Lentivirus/genetics ; Mice, Inbred NOD ; Transduction, Genetic/methods
    Chemical Substances Antigens, CD34 ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
    Language English
    Publishing date 2017-03-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2017.02.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells.

    Petrillo, Carolina / Thorne, Lucy G / Unali, Giulia / Schiroli, Giulia / Giordano, Anna M S / Piras, Francesco / Cuccovillo, Ivan / Petit, Sarah J / Ahsan, Fatima / Noursadeghi, Mahdad / Clare, Simon / Genovese, Pietro / Gentner, Bernhard / Naldini, Luigi / Towers, Greg J / Kajaste-Rudnitski, Anna

    Cell stem cell

    2018  Volume 23, Issue 6, Page(s) 820–832.e9

    Abstract: Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral ...

    Abstract Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently restricts VSV glycoprotein-mediated vector entry. Importantly, individual variability in endogenous IFITM3 levels correlated with permissiveness of HSCs to lentiviral transduction, suggesting that CsH treatment will be useful for improving ex vivo gene therapy and standardizing HSC transduction across patients. Overall, our work unravels the involvement of innate pathogen recognition molecules in immune blocks to gene correction in primary human HSCs and highlights how these roadblocks can be overcome to develop innovative cell and gene therapies.
    MeSH term(s) Animals ; Cell Line ; Cyclosporine/pharmacology ; Female ; Gene Editing ; HEK293 Cells ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Immunity, Innate/drug effects ; Lentivirus/drug effects ; Lentivirus/genetics ; Lentivirus/immunology ; Mice ; Mice, Inbred NOD ; Mice, Knockout ; Transduction, Genetic
    Chemical Substances Cyclosporine (83HN0GTJ6D) ; cyclosporin H (FUO6O3NDNH)
    Language English
    Publishing date 2018-11-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2018.10.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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