Vincenzo Bronte

Venetian Institute of Molecular Medicine, Padua, Veneto, Italy

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Publications (152)1086.14 Total impact

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    ABSTRACT: Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 06/2015; DOI:10.1016/j.immuni.2015.05.009 · 19.75 Impact Factor
  • Jordi Ochando, Patricia Conde, Vincenzo Bronte
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    ABSTRACT: Myeloid-derived suppressor cells (MDSC) are cells of myeloid origin with enhanced suppressive function. They are negative regulators of the immune responses and comprise a heterogeneous mixture of immunosuppressive cells of monocytic (M-MDSC) and granulocytic (G-MDSC) origin. A more recent nomenclature proposes the term “suppressive monocyte derived cells” (suppressive MCs) to define CSF1/CSF2-dependent mouse suppressor cells that develop from common monocyte progenitors (cMoPs) after birth. Here, we review the literature about monocytic-derived cells with demonstrated suppressor function in vitro and in vivo within the context of solid organ transplantation.
    06/2015; 2(2). DOI:10.1007/s40472-015-0054-9
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    ABSTRACT: In the Sp6 mouse plasmacytoma model, a whole cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced an anatomically localized and cytotoxic T cells (CTLs)-mediated protection against wild type (WT) Sp6. Both WT Sp6 and Sp6/B7 showed a down-regulated expression of MHC H-2 L(d) . Increase of H-2 L(d) expression by cDNA transfection (Sp6/B7/L(d) ) raised tumour immune protection and shifted most CTL responses towards H-2 L(d) -restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 L(d) -restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naïve mice, were detected in immunised mice as well as in splenocytes from naïve mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage associated molecular patterns (DAMPs). It has been shown that Toll like receptors (TLRs) triggering induces gp70 expression. DAMPs released by CTL-mediated killing of Sp6/B7-Sp6/B7/L(d) cells migrated to draining lymph nodes during immunisation may activate gp70 expression and presentation in most resident antigen presenting cells (APCs). The same could also apply for MuMLV virus particles present in Sp6-cytosol, discharged by dying cells and superinfecting APCs. The outcome of such a massive gp70 cross-presentation would likely be tolerogenic for the high affinity AH1-gp70-specific CTLs clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Immunology 05/2015; DOI:10.1111/imm.12477 · 3.74 Impact Factor
  • Ainhoa Arina, Vincenzo Bronte
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    ABSTRACT: Novel models of autochthonous tumorigenesis and adoptive T cell therapy (ATT) are providing new clues regarding the pro-tumorigenic and immunosuppressive effects of myeloid-derived suppressor cells (MDSC), and their interaction with T cells. New findings are shifting the perception of the main level at which MDSC act, from direct cell-to-cell suppression to others, such as limiting T cell infiltration. Adoptively transferred, high-avidity T cells recognizing peptides with high-affinity for MHC-I eliminated large tumors. However, low-avidity T cells or low-affinity peptides resulted in failure to eradicate tumors. Manipulation of intratumoral myeloid cells improved the outcome of otherwise unsuccessful ATT. Therefore, therapeutic intervention directed at the tumor stroma might be required when using suboptimal T cells for ATT. Copyright © 2015. Published by Elsevier Ltd.
    Current Opinion in Immunology 04/2015; 33. DOI:10.1016/j.coi.2015.02.006 · 7.87 Impact Factor
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    ABSTRACT: Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding "bystander" cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca2+-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy.
    Oncotarget 03/2015; · 6.63 Impact Factor
  • Vincenzo Bronte, Peter J Murray
    Nature Medicine 02/2015; 21(2):117-9. DOI:10.1038/nm.3794 · 28.05 Impact Factor
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    ABSTRACT: Myeloid-derived suppressor cells (MDSCs) have been shown to control self-reactive and anti-graft effector T-cells in autoimmunity and transplantation, but their therapeutic use is limited by their scarce availability in the peripheral blood of tumor-free donors. We isolated and characterized a novel population of myeloid suppressor cells, named fibrocytic MDSC (f-MDSC), which are differentiated from umbilical cord blood (UCB) precursors (Zoso et al., 2014). This MDSC subset promotes regulatory T-cell expansion and induces normoglycemia in a xenogeneic model of type 1 diabetes. Here we describe in details the experimental design and the bioinformatics analyses of the gene expression dataset used to investigate the molecular mechanisms at the base of MDSC tolerogenic and suppressive properties. We also provide an R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. Raw and pre-processed data are available at Gene Expression Omnibus under accession GSE52376.
    12/2014; 2. DOI:10.1016/j.gdata.2014.10.018
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    ABSTRACT: Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; DOI:10.1016/j.immuni.2014.10.020 · 19.75 Impact Factor
  • Vincenzo Bronte
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    ABSTRACT: Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) provide evidence suggesting that dendritic cells detect DNA from tumor cells via the STING-mediated, cytosolic DNA sensing pathway. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 11/2014; 41(5):679-681. DOI:10.1016/j.immuni.2014.11.004 · 19.75 Impact Factor
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    ABSTRACT: Study of myeloid cells endowed with suppressive activity is an active field of research which has particular importance in cancer, in view of the negative regulatory capacity of these cells to the host's immune response. The expansion of these cells, called myeloid-derived suppressor cells (MDSCs), has been documented in many models of tumor-bearing mice and in patients with tumors of various origin, and their presence is associated with disease progression and reduced survival. For this reason, monitoring this type of cell expansion is of clinical importance, and flow cytometry is the technique of choice for their identification. Over the years, it has been demonstrated that MDSCs comprise a group of immature myeloid cells belonging both to monocytic and granulocytic lineages, with several stages of differentiation; their occurrence depends on tumor-derived soluble factors, which guide their expansion and determine their block of differentiation. Because of their heterogeneous composition, accurate phenotyping of these cells requires a multicolor approach, so that the expansion of all MDSC subsets can be appreciated.This review article focuses on identifying MDSCs and discusses problems associated with phenotyping circulating and tumor-associated MDSCs in humans and in mouse models. This article is protected by copyright. All rights reserved.
    Cytometry Part B Clinical Cytometry 11/2014; 88(2). DOI:10.1002/cytob.21206 · 2.28 Impact Factor
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    ABSTRACT: By restraining T-cell activation and promoting Treg-cell expansion, myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (tDCs) can control self-reactive and anti-graft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor-free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC (f-MDSCs), which are differentiated from umbilical cord blood (UCB) precursors by 4-day culture with FDA-approved cytokines (rh-GM-CSF and rh-G-CSF). This MDSC subset, characterized by the expression of MDSC-, DC-, and fibrocyte-associated markers, promotes Treg-cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes (T1D). In order to exert their pro-tolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection.This article is protected by copyright. All rights reserved
    European Journal of Immunology 11/2014; 44(11). DOI:10.1002/eji.201444522 · 4.52 Impact Factor
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    ABSTRACT: We analyzed the interactions between primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs.
    08/2014; 4(1). DOI:10.4161/21592527.2014.955386
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    ABSTRACT: Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, and its synthetic analog Trehalose-6,6-dibehenate (TDB) bind to the C-type lectin receptors macrophage-inducible C-type lectin (Mincle) and Mcl to activate macrophages. Genetically, the transcriptional response to TDB/TDM has been defined to require FcRγ-Syk-Card9 signaling. However, TDB/TDM-triggered kinase activation has not been studied well, and it is largely unknown which transcriptional regulators bring about inflammatory gene expression. In this article, we report that TDB/TDM caused only weak Syk-phosphorylation in resting macrophages, consistent with low basal Mincle expression. However, LPS-priming caused MYD88-dependent upregulation of Mincle, resulting in enhanced TDB/TDM-induced kinase activation and more rapid inflammatory gene expression. TLR-induced Mincle expression partially circumvented the requirement for Mcl in the response to TDB/TDM. To dissect transcriptional responses to TDB/TDM, we mined microarray data and identified early growth response (Egr) family transcription factors as direct Mincle target genes, whereas upregulation of Cebpb and Hif1a required new protein synthesis. Macrophages and dendritic cells lacking C/EBPβ showed nearly complete abrogation of TDB/TDM responsiveness, but also failed to upregulate Mincle. Retroviral rescue of Mincle expression in Cebpb-deficient cells restored induction of Egr1, but not of G-CSF. This pattern of C/EBPβ dependence was also observed after stimulation with the Dectin-1 ligand Curdlan. Inducible expression of hypoxia-inducible factor 1α (HIF1α) also required C/EBPβ. In turn, HIF1α was not required for Mincle expression, kinase activation, and Egr1 or Csf3 expression, but critically contributed to NO production. Taken together, we identify C/EBPβ as central hub in Mincle expression and inflammatory gene induction, whereas HIF1α controls Nos2 expression. C/EBPβ also connects TLR signals to cord factor responsiveness through MYD88-dependent upregulation of Mincle.
    The Journal of Immunology 08/2014; 193(7). DOI:10.4049/jimmunol.1301593 · 5.36 Impact Factor
  • Vincenzo Bronte
    Immunology and Cell Biology 08/2014; 92(8). DOI:10.1038/icb.2014.67 · 4.21 Impact Factor
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    ABSTRACT: The dynamic interplay between cancer and host immune system often affects the process of myelopoiesis. As a consequence, tumor-derived factors sustain the accumulation and functional differentiation of myeloid cells, including myeloid-derived suppressor cells (MDSCs), which can interfere with T cell-mediated responses. Since both the phenotype and mechanisms of action of MDSCs appear to be tumor-dependent, it is important not only to determine the presence of all MDSC subsets in each cancer patient, but also which MDSC subsets have clinical relevance in each tumor environment. In this review, we describe the differences between MDSC populations expanded within different tumor contexts and evaluate the prognostic significance of MDSC expansion in peripheral blood and within tumor masses of neoplastic patients.
    Annals of the New York Academy of Sciences 06/2014; 1319(1):47-65. DOI:10.1111/nyas.12469 · 4.31 Impact Factor
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    ABSTRACT: INTRODUCTION: Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant neoplasm of epithelial origin which represents one of the major causes of death in the western world. At present, the Tumor Tissue Microenvironment (TME) is supposed to play a pivotal role on the aggressiveness of pancreatic epithelial tumor cells. Aim of this study was to investigate the interactions between PDAC cells (derived from patients who underwent surgical treatment) and different biocompatible scaffolds to generate new 3D in vitro models for TME studies. METHODS: To create 3D cellular models, three scaffolds were fabricated with different polymers and techniques: polyvinyl alcohol/gelatin (PVA/G; weight composition ratio of 70/30) obtained via emulsion and freeze-drying; poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) produced via either compression molding and particle leaching (namely, CM) or electrospinning (namely, ES). Human epithelial primary cultures were derived from PDAC explants. Both tissues and derived cells were genetically characterized for K-ras and TP53. PDAC cells were seeded on the sterile scaffolds at a density of 1×104 cells/mm3 and cultured for 9 days in complete RMPI medium. Sample characterization included: cell viability (using the AlamarBlue assay), cell morphology [via scanning electron microscopy (SEM) and histology with H&E staining), expression of MMP9 and MMP2 proteins via Western Blot (WB) and immunohistochemistry (IHC). RESULTS: At the endpoint cells were found to be viable in the scaffolds showing AlamarBlue reduction of 47.5% (PVA/G), 40.6% (PEOT/PBT_CM) and 45.1% (PEOT/PBT_ES). SEM analysis detected a good 3D colonization and a very strong cellular adhesion in all three models. The histologic analysis highlighted the formation of PDAC clusters showing a ductal-like morphology only in the PVA/G model. Finally, in the 3D models, a higher expression of MMP9 and MMP2 proteins was observed with respect to 2D cell cultures. DISCUSSION: From our findings, the development of 3D cancer tissue-engineered models using biocompatible scaffolds for cell growth seems to be feasible, versatile, low time consuming and representative of PDAC features. This platform could be used as a preliminary attempt before in vivo testing. In the close future, 3D models could be used to screen experimental pharmacological treatments for the modulation of different tumor proteins. Furthermore, in these 3D models an integration among different cellular types involved in PDAC microenvironment could be generated and be more representative of the human TME than the in vitro models used so far.
    48th Annual Meeting of the Pancreas Club, Westin Lombard Chicago IL; 05/2014
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    ABSTRACT: Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy.
    Journal of Experimental Medicine 04/2014; DOI:10.1084/jem.20131916 · 13.91 Impact Factor
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    ABSTRACT: Tumor microenvironment of solid tumors is characterized by a strikingly high concentration of adenosine and ATP. Physiological significance of this biochemical feature is unknown, but it has been suggested that it may affect infiltrating immune cell responses and tumor progression. There is increasing awareness that many of the effects of extracellular ATP on tumor and inflammatory cells are mediated by the P2X7 receptor (P2X7R). Aim of this study was to investigate whether: (i) extracellular ATP is a component of neuroblastoma (NB) microenvironment, (ii) myeloid-derived suppressor cells (MDSCs) express functional P2X7R and (iii) the ATP/P2X7R axis modulates MDSC functions. Our results show that extracellular ATP was detected in NB microenvironment in amounts that increased in parallel with tumor progression. The percentage of CD11b(+)/Gr-1(+) cells was higher in NB-bearing mice compared with healthy animals. Within the CD11b/Gr-1(+) population, monocytic MDSCs (M-MDSCs) produced higher levels of reactive oxygen species (ROS), arginase-1 (ARG-1), transforming growth factor-β1 (TGF-β1) and stimulated more potently in vivo tumor growth, as compared with granulocytic MDSCs (G-MDSCs). P2X7R of M-MDSCs was localized at the plasma membrane, coupled to increased functionality, upregulation of ARG-1, TGF-β1 and ROS. Quite surprisingly, the P2X7R in primary MDSCs as well as in the MSC-1 and MSC-2 lines was uncoupled from cytotoxicity. This study describes a novel scenario in which MDSC immunosuppressive functions are modulated by the ATP-enriched tumor microenvironment.
    Cell Death & Disease 03/2014; 5(3):e1135. DOI:10.1038/cddis.2014.109 · 5.18 Impact Factor
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    ABSTRACT: Under many inflammatory contexts, such as tumor progression, systemic and peripheral immune response is tailored by reactive nitrogen species (RNS)-dependent post-translational modifications, suggesting a biological function for these chemical alterations. RNS modify both soluble factors and receptors essential to induce and maintain a tumor-specific immune response, creating a "chemical barrier" that impairs effector T cell infiltration and functionality in tumor microenvironment and supports the escape phase of cancer. RNS generation during tumor growth mainly depends on nitric oxide production by both tumor cells and tumor-infiltrating myeloid cells that constitutively activate essential metabolic pathways of l-arginine catabolism. This review provides an overview of the potential immunological and biological role of RNS-induced modifications and addresses new approaches targeting RNS either in search of novel biomarkers or to improve anti-cancer treatment.
    Frontiers in Immunology 02/2014; 5:69. DOI:10.3389/fimmu.2014.00069
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    ABSTRACT: The present study employed mass sequencing of small RNA libraries to identify the repertoire of small noncoding RNAs expressed in normal CD4+ T-cells compared to cells transformed with human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma (ATLL). Results revealed distinct patterns of microRNA expression in HTLV-1-infected CD4+ T-cell lines with respect to their normal counterparts. In addition, a search for viral-encoded microRNAs yielded 2 sequences that originated from the plus strand of the HTLV-1 genome. Several sequences derived from tRNAs were expressed at substantial levels in both uninfected and infected cells. One of the most abundant tRNA fragments (tRF-3019) was derived from the 3' end of tRNA-proline. tRF-3019 exhibited perfect sequence complementarity to the primer binding site of HTLV-1. Results of an in vitro reverse transcriptase assay verified that tRF-3019 was capable of priming HTLV-1 reverse transcriptase. Both tRNA-proline and tRF-3019 were detected in virus particles isolated from HTLV-1-infected cells. These findings suggest that tRF-3019 may play an important role in priming HTLV-1 reverse transcription and could thus represent a novel target to control HTLV-1 infection.
    Journal of Virology 01/2014; DOI:10.1128/JVI.02823-13 · 4.65 Impact Factor

Publication Stats

10k Citations
1,086.14 Total Impact Points

Institutions

  • 2015
    • Venetian Institute of Molecular Medicine
      Padua, Veneto, Italy
  • 2011–2015
    • University of Verona
      • • Department of Pathology
      • • Section of Immunology
      Verona, Veneto, Italy
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
    • Center of Molecular Immunology
      La Habana, Ciudad de La Habana, Cuba
  • 2012
    • University of Milan
      • Department of Medical Biotechnology and Translational Medicine
      Milano, Lombardy, Italy
  • 1999–2012
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 2007–2011
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
    • New York State
      New York City, New York, United States
  • 1989–2011
    • University of Padova
      • • Dipartimento di Scienze Mediche e Chirurgiche
      • • Department of Biomedical Sciences - DSB
      Padua, Veneto, Italy
  • 2006–2010
    • Istituto Oncologico Veneto
      Padua, Veneto, Italy
  • 2004
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2002–2004
    • University-Hospital of Padova
      Padua, Veneto, Italy
  • 1995–1999
    • National Institutes of Health
      • • Branch of Surgery
      • • Branch of Experimental Immunology
      Maryland, United States
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1997
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 1995–1996
    • National Cancer Institute (USA)
      • Surgery Branch
      Bethesda, MD, United States
  • 1992–1995
    • It-Robotics
      Vicenza, Veneto, Italy
  • 1994
    • University of Ferrara
      Ferrare, Emilia-Romagna, Italy