المؤلفون: Happy Kurnia Permatasari, Shingo Nakahata, Tomonaga Ichikawa, Yanuar Rahmat Fauzi, Hiroshi Kiyonari, Kotaro Shide, Takuro Kameda, Kazuya Shimoda, Masaya Ono, Tomohiko Taki, Masafumi Taniwaki, Mitsuru Futakuchi, Kazuhiro Morishita

المصدر: Experimental hematology. 111

مصطلحات موضوعية: Cancer Research, Human T-lymphotropic virus 1, Carcinogenesis, Tumor Suppressor Proteins, Cell Biology, Hematology, Gene Products, tax, Repressor Proteins, Mice, Genetics, Animals, Humans, Leukemia-Lymphoma, Adult T-Cell, Protein Isoforms, Genes, Tumor Suppressor, Molecular Biology

الوصف: B-Cell leukemia/lymphoma 11B (BCL11B) is a transcription factor important for T-cell development and acts as a tumor suppressor gene in T-cell acute lymphoblastic leukemia. Here, we identified BCL11B as a candidate leukemia-associated gene in human T-cell leukemia virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma (ATLL). Interestingly, the short form lacking exon 3 (BCL11B/S) protein was more highly expressed than the full-length BCL11B (BCL11B/L) in leukemic cells from most of the ATLL patients, although expression ratios of BCL11B/L to BCL11B/S were almost equal in control CD4

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::05b9d59b1304606f76e4d470e8240ebeTest
https://pubmed.ncbi.nlm.nih.gov/35421541Test

المؤلفون: Takaharu Ueno, Tadaki Suzuki, Sameh Lotfi, Masateru Hiyoshi, Jutatip Panaampon, Shinya Suzu, Atae Utsunomiya, Osamu Noyori, Masahito Tokunaga, Yorifumi Satou, Hideki Hasegawa, Jun-ichi Fujisawa, Naofumi Takahashi, Seiji Okada, Yuetsu Tanaka, Masao Matsuoka, Yuko Sato, Youssef M. Eltalkhawy, Jun-ichirou Yasunaga

المصدر: PLoS Pathogens, Vol 17, Iss 11, p e1010126 (2021)
PLoS Pathogens

مصطلحات موضوعية: RNA viruses, Physiology, viruses, Cell Membranes, Mice, SCID, Pathology and Laboratory Medicine, medicine.disease_cause, White Blood Cells, Mice, Immunodeficiency Viruses, Animal Cells, Cell Movement, Mice, Inbred NOD, Immune Physiology, Medicine and Health Sciences, Biology (General), Human T-lymphotropic virus 1, Gene knockdown, T Cells, Chemistry, Cell migration, Animal Models, Gene Products, tax, Cell biology, Leukemia, medicine.anatomical_structure, Experimental Organism Systems, Medical Microbiology, Viral Pathogens, Viruses, Tumor Necrosis Factors, Pathogens, Cellular Types, Cellular Structures and Organelles, Research Article, Viral protein, QH301-705.5, Immune Cells, Immunology, Viral transmission, Mouse Models, Spleen, Research and Analysis Methods, Microbiology, Model Organisms, Virology, Retroviruses, Genetics, medicine, Viral structural protein, Animals, Humans, Luciferase, Animal Models of Disease, Microbial Pathogens, Molecular Biology, Viral Structural Proteins, Blood Cells, Biology and life sciences, Lentivirus, Cell Membrane, Organisms, HIV, Htlv-1, Cell Biology, RC581-607, medicine.disease, HTLV-I Infections, Coculture Techniques, Animal Models of Infection, Disease Models, Animal, Animal Studies, HIV-1, Parasitology, Immunologic diseases. Allergy, Viral Transmission and Infection

الوصف: Human T-cell leukemia virus type 1 (HTLV-1) infects target cells primarily through cell-to-cell routes. Here, we provide evidence that cellular protein M-Sec plays a critical role in this process. When purified and briefly cultured, CD4+ T cells of HTLV-1 carriers, but not of HTLV-1- individuals, expressed M-Sec. The viral protein Tax was revealed to mediate M-Sec induction. Knockdown or pharmacological inhibition of M-Sec reduced viral infection in multiple co-culture conditions. Furthermore, M-Sec knockdown reduced the number of proviral copies in the tissues of a mouse model of HTLV-1 infection. Phenotypically, M-Sec knockdown or inhibition reduced not only plasma membrane protrusions and migratory activity of cells, but also large clusters of Gag, a viral structural protein required for the formation of viral particles. Taken together, these results suggest that M-Sec induced by Tax mediates an efficient cell-to-cell viral infection, which is likely due to enhanced membrane protrusions, cell migration, and the clustering of Gag.
Author summary In the present study, we identified the cellular protein M-Sec as a host factor necessary for de novo infection of human T-cell leukemia virus type 1 (HTLV-1), the causative retrovirus of an aggressive blood cancer known as adult T-cell leukemia/lymphoma. The inhibition or knockdown of M-Sec in infected cells resulted in a reduced viral infection in several culture models and a mouse model. We recently demonstrated a similar role of M-Sec in macrophages infected with another human retrovirus HIV-1, but it has been generally thought that M-Sec is not related to HTLV-1 infection because of the lack of its expression in CD4+ T cells, the major target of HTLV-1. In this study, we revealed that CD4+ T cells of HTLV-1 asymptomatic carriers, but not those of HTLV-1- individuals, expressed M-Sec, and that the viral protein Tax mediated the induction of M-Sec. Thus, M-Sec is a new and useful tool for further understanding the process of HTLV-1 transmission.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b0e3a0d3056e69b73d59aa89657273a4Test
https://doaj.org/article/4db740f1dab34a8785d70fd6f201bafbTest

المؤلفون: Helen Kiik, Saumya Ramanayake, Michi Miura, Yuetsu Tanaka, Anat Melamed, Charles R.M. Bangham

المصدر: PLOS Pathogens. 18:e1010387

مصطلحات موضوعية: Transcriptional Activation, Human T-lymphotropic virus 1, Proviruses, Virology, Immunology, NF-kappa B, Genetics, Humans, Parasitology, Gene Products, tax, Molecular Biology, Microbiology

الوصف: The human T-cell leukemia virus type 1 (HTLV-1) transactivator protein Tax has pleiotropic functions in the host cell affecting cell-cycle regulation, DNA damage response pathways and apoptosis. These actions of Tax have been implicated in the persistence and pathogenesis of HTLV-1-infected cells. It is now known that tax expression occurs in transcriptional bursts of the proviral plus-strand, but the effects of the burst on host transcription are not fully understood. We carried out RNA sequencing of two naturally-infected T-cell clones transduced with a Tax-responsive Timer protein, which undergoes a time-dependent shift in fluorescence emission, to study transcriptional changes during successive phases of the HTLV-1 plus-strand burst. We found that the transcriptional regulation of genes involved in the NF-κB pathway, cell-cycle regulation, DNA damage response and apoptosis inhibition were immediate effects accompanying the plus-strand burst, and are limited to the duration of the burst. The results distinguish between the immediate and delayed effects of HTLV-1 reactivation on host transcription, and between clone-specific effects and those observed in both clones. The major transcriptional changes in the infected host T-cells observed here, including NF-kB, are transient, suggesting that these pathways are not persistently activated at high levels in HTLV-1-infected cells. The two clones diverged strongly in their expression of genes regulating the cell cycle. Up-regulation of senescence markers was a delayed effect of the proviral plus-strand burst and the up-regulation of some pro-apoptotic genes outlasted the burst. We found that activation of the arylhydrocarbon receptor (AhR) pathway enhanced and prolonged the proviral burst, but did not increase the rate of reactivation. Our results also suggest that sustained plus-strand expression is detrimental to the survival of infected cells.Author SummaryHuman T-cell leukemia virus type 1 (HTLV-1) causes a lifelong infection that results in disease in ∼10% of cases. The HTLV-1 transactivator protein Tax is involved in both the persistence of infected host cells, and the pathogenesis of HTLV-1 infection. tax is transcribed from the plus-strand of the provirus, and tax expression is not constitutive, but limited to transcriptional bursts. How these bursts affect host cell transcription is not completely understood. Here, we studied the temporal changes in host transcription during successive phases of the plus-strand burst in two naturally-infected T-cell clones. We found that the deregulation of genes involved in Tax-associated processes, including NF-κB activation, cell-cycle regulation, DNA damage response and suppression of apoptosis, coincided with the early phase of the plus-strand burst: these transcriptional effects appear to be limited to the duration of the proviral plus-strand expression. Regulation of cell-cycle genes diverged between the clones, demonstrating the heterogeneity of naturally-infected cells. We observed a pro-apoptotic response, which outlasted the burst and may indicate increased risk of apoptosis following the burst. Finally, we observed that AhR activity regulated the intensity and duration of the burst, but not the dynamics of reactivation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5f43586f6a958e75ac4ccf40e772b39Test
https://doi.org/10.1371/journal.ppat.1010387Test

المؤلفون: Charles R. M. Bangham, Masao Matsuoka, Anat Melamed, Kisato Nosaka, Jun-ichirou Yasunaga, Yasuhiko Sugawara, Hayato Utsunomiya, Takafumi Shichijo, Yukihiro Inomata, Asami Yamada, Hirofumi Akari, Mikiko Izaki, Kenji Sugata, Youko Suehiro, Taizo Hibi

المصدر: PLoS Pathogens, Vol 17, Iss 2, p e1009271 (2021)
PLoS Pathogens

مصطلحات موضوعية: Male, RNA viruses, Physiology, T-Lymphocytes, Artificial Gene Amplification and Extension, CD8-Positive T-Lymphocytes, Monkeys, Virus Replication, Pathology and Laboratory Medicine, Biochemistry, Polymerase Chain Reaction, White Blood Cells, 0302 clinical medicine, Proviruses, Animal Cells, Immune Physiology, Medicine and Health Sciences, Leukemia-Lymphoma, Adult T-Cell, Cytotoxic T cell, Biology (General), Immune Response, Mammals, Human T-lymphotropic virus 1, 0303 health sciences, Immune System Proteins, biology, T Cells, Hematopoietic Stem Cell Transplantation, Eukaryota, Gene Products, tax, Middle Aged, Viral Load, Provirus, Leukemia, Medical Microbiology, Viral Pathogens, 030220 oncology & carcinogenesis, Viruses, Vertebrates, Female, Pathogens, Cellular Types, Antibody, Macaque, Research Article, Adult, Primates, QH301-705.5, Immune Cells, Immunology, Cytotoxic T cells, Research and Analysis Methods, Microbiology, Antibodies, Virus, Macaca fuscata, 03 medical and health sciences, Immune system, Antigen, Virology, Retroviruses, Old World monkeys, Genetics, medicine, Animals, Humans, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, 030304 developmental biology, Blood Cells, Organisms, Biology and Life Sciences, Proteins, Dendritic Cells, Htlv-1, Cell Biology, RC581-607, medicine.disease, HTLV-I Infections, Clone Cells, Liver Transplantation, Amniotes, biology.protein, Natural Killer T-Cells, Parasitology, Immunologic diseases. Allergy, Zoology, CD8, Cloning

الوصف: Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression.
Author summary HTLV-1 spreads in vivo through two routes: de novo infection and clonal proliferation of infected cells. Reverse transcriptase inhibitors and integrase inhibitors do not influence the PVL in HTLV-1-infected individuals, indicating that clonal proliferation is dominant to maintain and increase PVL in vivo in the chronic phase. It is assumed that the host immune responses are critical factors for clonal proliferation. We found that HTLV-1-infected clones dramatically changed during de novo infection whereas the clones in the chronic phase survived long-term after transplantation, indicating that HTLV-1-infected clones are selected for survival in vivo. Surprisingly, depletion of CD8+ cells had a small impact on PVL in a STLV-1 infected Japanese macaque, but modified the clonality of infected cells. The cells after depletion of CD8+ cells showed a higher proliferative activity during short-term in vitro culture. This study reveals that intrinsic attributes of selected clones contribute to clonal proliferation of infected cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b3c50ded3eeb2091998a044bbb97260cTest
https://doaj.org/article/aa6ab0195b1d47f492253da164ea1e2fTest

المؤلفون: Hiba El Hajj, Rita Hleihel, Abdou Akkouche, Ali Bazarbachi, Séverine Chambeyron, Hala Skayneh, Sara Moodad

المساهمون: American University of Beirut [Beyrouth] (AUB), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

المصدر: PLoS Pathogens
PLoS Pathogens, Public Library of Science, 2021, 17 (1), pp.e1009219. ⟨10.1371/journal.ppat.1009219⟩
PLoS Pathogens, Vol 17, Iss 1, p e1009219 (2021)

مصطلحات موضوعية: RNA viruses, Life Cycles, Hemocytes, T-cell leukemia, Retroviridae Proteins, Pathology and Laboratory Medicine, Biochemistry, White Blood Cells, RNA interference, Larvae, 0302 clinical medicine, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Biology (General), Cellular Senescence, Regulation of gene expression, Human T-lymphotropic virus 1, 0303 health sciences, biology, Drosophila Melanogaster, EZH2, Eukaryota, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Animal Models, Gene Products, tax, Precipitation Techniques, 3. Good health, Cell biology, Nucleic acids, Insects, Basic-Leucine Zipper Transcription Factors, Genetic interference, Experimental Organism Systems, Medical Microbiology, Viral Pathogens, 030220 oncology & carcinogenesis, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Epigenetics, Drosophila, Cellular Types, Anatomy, Pathogens, PRC2, Research Article, Gene Expression Regulation, Viral, Arthropoda, QH301-705.5, Immune Cells, Transgene, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Research and Analysis Methods, Transfection, Microbiology, 03 medical and health sciences, Model Organisms, Ocular System, Virology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retroviruses, Genetics, Animals, Immunoprecipitation, Humans, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Transcription factor, 030304 developmental biology, Blood Cells, Biology and life sciences, Organisms, Cell Biology, Htlv-1, RC581-607, Invertebrates, HTLV-I Infections, Animal Studies, biology.protein, RNA, Eyes, Parasitology, Gene expression, Immunologic diseases. Allergy, Head, Zoology, Entomology, Developmental Biology, HeLa Cells

الوصف: Adult T cell leukemia (ATL) is an aggressive malignancy secondary to chronic infection by the human T-cell leukemia virus type 1 (HTLV-1) infection. Two viral proteins, Tax and HBZ, play central roles in ATL leukemogenesis. Tax expression transforms T cells in vitro and induces ATL-like disease in mice. Tax also induces a rough eye phenotype and increases hemocyte count in Drosophila melanogaster, indicative of transformation. Among multiple functions, Tax modulates the expression of the enhancer of zeste homolog 2 (EZH2), a methyltransferase of the Polycomb Repressive Complex 2 (PRC2), leading to H3K27me3-dependent reprogramming of around half of cellular genes. HBZ is a negative regulator of Tax-mediated viral transcription. HBZ effects on epigenetic signatures are underexplored. Here, we established an hbz transgenic fly model, and demonstrated that, unlike Tax, which induces NF-κB activation and enhanced PRC2 activity creating an activation loop, HBZ neither induces transformation nor NF-κB activation in vivo. However, overexpression of Tax or HBZ increases the PRC2 activity and both proteins directly interact with PRC2 complex core components. Importantly, overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB or PRC2 activation and totally rescues Tax-induced transformation and senescence. Our results establish the in vivo antagonistic effect of HBZ on Tax-induced transformation and cellular effects. This study helps understanding long-term HTLV-1 persistence and cellular transformation and opens perspectives for new therapeutic strategies targeting the epigenetic machinery in ATL.
Author summary Adult T cell leukemia-lymphoma is an aggressive hematological malignancy, caused by the retroviral infection with HTLV-1. Tax and HBZ play critical roles in leukemia development. Tax activates the NF-κB pathway and modulates the epigenetic machinery to induce cellular proliferation and malignant transformation. We generated hbz or tax/hbz transgenic fly models and explored the phenotypes and epigenetic changes in vivo. Unlike Tax, HBZ expression failed to activate NF-κB or to induce transformation or senescence in vivo, yet activated PRC2 core components resulting in subsequent epigenetic changes. HBZ expression in tax Tg flies inhibits Tax-induced NF-κB or PRC2 activation, resulting in inhibition of malignant cellular proliferation and its consequent senescence. Our study proves the antagonistic effect of HBZ on Tax-induced transformation in vivo, providing further understanding on ATL pathogenesis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c543f8201aa64eeb246b79696cc85afTest
https://hal.archives-ouvertes.fr/hal-03147929/file/journal.ppat.1009219.pdfTest

المؤلفون: Vandermeulen, Charlotte, O’grady, Tina, Wayet, Jerome, Galvan, Bartimee, Maseko, Sibusiso, Cherkaoui, Majid, Desbuleux, Alice, Coppin, Georges, Olivet, Julien, Ben Ameur, Lamya, Kataoka, Keisuke, Ogawa, Seishi, Hermine, Olivier, Marcais, Ambroise, Thiry, Marc, Mortreux, Franck, Calderwood, Michael, van Weyenbergh, Johan, Peloponese, Jean-Marie, Charloteaux, Benoit, van den Broeke, Anne, Hill, David E., Vidal, Marc, Dequiedt, Franck, Twizere, Jean-Claude

المساهمون: GIGA [Université Liège], Université de Liège, Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Kyoto University, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Liège (CHU-Liège), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), PELOPONESE, Jean-Marie

المصدر: PLoS Pathogens
PLoS Pathogens, 2021, 17 (9), pp.e1009919. ⟨10.1371/journal.ppat.1009919⟩
PLoS Pathogens, Vol 17, Iss 9, p e1009919 (2021)
P L o S Pathogens, 17 (9

مصطلحات موضوعية: RNA viruses, Interaction Networks, Retroviridae Proteins, LEUKEMIA-VIRUS TYPE-1, RNA-binding proteins, Virologie générale, Pathology and Laboratory Medicine, Biochemistry, ACTIVATION, Jurkat Cells, White Blood Cells, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunologie, BINDING, Medicine and Health Sciences, Leukemia-Lymphoma, Adult T-Cell, CD45, NETWORK, Biology (General), GENE-EXPRESSION, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Parasitologie, Human T-lymphotropic virus 1, T Cells, Gene Products, tax, Genomics, PROTEIN INTERACTS, Nucleic acids, TRANSCRIPTION FACTORS, Basic-Leucine Zipper Transcription Factors, Oncology, Medical Microbiology, Viral Pathogens, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pathogens, Cellular Types, Biologie, Life Sciences & Biomedicine, Transcriptome Analysis, Research Article, QH301-705.5, RNA Splicing, Immune Cells, Immunology, Microbiology, Virology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retroviruses, Genetics, Humans, RNA, Messenger, Microbial Pathogens, Molecular Biology, Science & Technology, Blood Cells, Biology and life sciences, Virologie médicale, RECOGNITION, Organisms, Biologie moléculaire, Cancers and Neoplasms, Proteins, Computational Biology, Htlv-1, Cell Biology, RC581-607, Splicing Factor U2AF, Genome Analysis, HTLV-I Infections, Alternative Splicing, HEK293 Cells, RNA processing, T-CELLS, RNA, Parasitology, Gene expression, Immunologic diseases. Allergy, Microbiologie et protistologie [bacteriol.virolog.mycolog.]

الوصف: Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.
SCOPUS: ar.j
info:eu-repo/semantics/published

وصف الملف: Electronic-eCollection; 1 full-text file(s): application/pdf; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::949667cb1a24868a4354d9ff33baa466Test
https://hal.science/hal-03400504/documentTest

المؤلفون: Adele Caterino-de-Araujo, Karoline Rodrigues Campos

المصدر: Infection, Genetics and Evolution. 96:105141

مصطلحات موضوعية: Microbiology (medical), Human T-lymphotropic virus 1, biology, Human T-lymphotropic virus 2, Virion, Gene Products, tax, Human T-lymphotropic virus, biology.organism_classification, HTLV-I Infections, Microbiology, Virology, Infectious Diseases, Genetics, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d271538135f9440a8fbe6d3a68a0c753Test
https://doi.org/10.1016/j.meegid.2021.105141Test

المؤلفون: Xin Guo, Huijun Zhi, Hampus Alexander Anders Engstrom, Nagesh Pasupala, Chou-Zen Giam, Yik-Khuan Ho, Oliver John Semmes

المصدر: PLoS Pathogens
PLoS Pathogens, Vol 16, Iss 5, p e1008618 (2020)

مصطلحات موضوعية: Genome instability, RNA viruses, DNA Repair, T-cell leukemia, Gene Identification and Analysis, Genetic Networks, Pathology and Laboratory Medicine, Biochemistry, White Blood Cells, Ubiquitin, Animal Cells, Medicine and Health Sciences, Macromolecular Structure Analysis, Leukemia-Lymphoma, Adult T-Cell, DNA Breaks, Double-Stranded, Biology (General), 0303 health sciences, Human T-lymphotropic virus 1, T Cells, 030302 biochemistry & molecular biology, Gene Products, tax, Cell biology, Ubiquitin ligase, Neoplasm Proteins, Nucleic acids, DNA-Binding Proteins, Medical Microbiology, Viral Pathogens, Viruses, Pathogens, Cellular Types, Network Analysis, Research Article, Computer and Information Sciences, Protein Structure, DNA repair, DNA damage, QH301-705.5, Immune Cells, Ubiquitin-Protein Ligases, Immunology, Immunoblotting, Molecular Probe Techniques, Down-Regulation, Biology, Research and Analysis Methods, Microbiology, Genomic Instability, 03 medical and health sciences, Virology, Retroviruses, Genetics, Humans, Molecular Biology Techniques, Transcription factor, Microbial Pathogens, Molecular Biology, 030304 developmental biology, Blood Cells, Biology and life sciences, Organisms, Proteins, Htlv-1, DNA, Cell Biology, RC581-607, HTLV-I Infections, Viral Replication, MDC1, biology.protein, Parasitology, Immunologic diseases. Allergy, Protein Structure Networks, HeLa Cells

الوصف: The genomic instability associated with adult T cell leukemia/lymphoma (ATL) is causally linked to Tax, the HTLV-1 viral oncoprotein, but the underlying mechanism is not fully understood. We have previously shown that Tax hijacks and aberrantly activates ring finger protein 8 (RNF8) — a lysine 63 (K63)-specific ubiquitin E3 ligase critical for DNA double-strand break (DSB) repair signaling — to assemble K63-linked polyubiquitin chains (K63-pUbs) in the cytosol. Tax and the cytosolic K63-pUbs, in turn, initiate additional recruitment of linear ubiquitin assembly complex (LUBAC) to produce hybrid K63-M1 pUbs, which trigger a kinase cascade that leads to canonical IKK:NF-κB activation. Here we demonstrate that HTLV-1-infected cells are impaired in DNA damage response (DDR). This impairment correlates with the induction of microscopically visible nuclear speckles by Tax known as the Tax-speckle structures (TSS), which act as pseudo DNA damage signaling scaffolds that sequester DDR factors such as BRCA1, DNA-PK, and MDC1. We show that TSS co-localize with Tax, RNF8 and K63-pUbs, and their formation depends on RNF8. Tax mutants defective or attenuated in inducing K63-pUb assembly are deficient or tempered in TSS induction and DDR impairment. Finally, our results indicate that loss of RNF8 expression reduces HTLV-1 viral gene expression and frequently occurs in ATL cells. Thus, during HTLV-1 infection, Tax activates RNF8 to assemble nuclear K63-pUbs that sequester DDR factors in Tax speckles, disrupting DDR signaling and DSB repair. Down-regulation of RNF8 expression is positively selected during infection and progression to disease, and further exacerbates the genomic instability of ATL.
Author summary Approximately 3–5% of HTLV-1-infected individuals develop an intractable malignancy called adult T cell leukemia/lymphoma (ATL) decades after infection. Unlike other leukemia, ATL is characterized by extensive genomic instability. Here we show that the genomic instability of ATL is associated with the hijacking and aberrant activation of a molecule known as ring finger protein 8 (RNF8) by HTLV-1 for viral replication. RNF8 is crucial for initiating the cellular DNA damage response (DDR) required for the repair of DNA double-strand breaks (DSBs), the most deleterious DNA damage. Its dysregulation in HTLV-1-infected cells results in the formation of pseudo DNA damage signaling scaffolds known as Tax speckle structures that sequester critical repair factors, causing an inability to repair DSBs efficiently. We have further found that loss of RNF8 expression reduces HTLV-1 viral replication and frequently occurs in ATL of all types. This likely facilitates the immune evasion of virus-infected cells, but degrades their ability to repair DSBs and exacerbates the genomic instability of ATL cells. Since DDR defects impact cancer response to DNA-damaging radiation and chemotherapies, RNF8 deficiency in ATL may be exploited for disease treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d223e40411d353d4523a7706c165720Test
http://europepmc.org/articles/PMC7274470Test

المؤلفون: Ki Ryang Koh, Mohamed Mahmoud Ahmed Mahgoub, Hirofumi Akari, Yusuke Higuchi, Charles R. M. Bangham, Masao Matsuoka, Takaharu Ueno, Anat Melamed, Jun-ichi Fujisawa, Masakazu Shimizu, Akatsuki Saito, Norihiro Takenouchi, Kenji Sugata, Jun-ichirou Yasunaga, Fumihiko Matsuda, Michi Miura, Rie Furuta

المساهمون: Medical Research Council (MRC)

المصدر: PLoS Pathogens
PLoS Pathogens, Vol 13, Iss 11, p e1006722 (2017)

مصطلحات موضوعية: RNA viruses, 0301 basic medicine, Neutrophils, viruses, Cellular differentiation, CD8-Positive T-Lymphocytes, Pathology and Laboratory Medicine, Monocytes, White Blood Cells, 0302 clinical medicine, Animal Cells, 1108 Medical Microbiology, immune system diseases, Medicine and Health Sciences, Cytotoxic T cell, Biology (General), Cells, Cultured, Human T-lymphotropic virus 1, T Cells, virus diseases, Cell Differentiation, Gene Products, tax, Leukemia, Haematopoiesis, medicine.anatomical_structure, Medical Microbiology, 1107 Immunology, Viral Pathogens, 030220 oncology & carcinogenesis, Viruses, Pathogens, Cellular Types, Stem cell, Research Article, 0605 Microbiology, QH301-705.5, Immune Cells, Immunology, Cytotoxic T cells, Bone Marrow Cells, Biology, Research and Analysis Methods, Microbiology, Virus, 03 medical and health sciences, Virology, Retroviruses, Genetics, medicine, Animals, Humans, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Blood Cells, Biology and life sciences, Organisms, Htlv-1, Cell Biology, RC581-607, Hematopoietic Stem Cells, medicine.disease, HTLV-I Infections, Macaca mulatta, 030104 developmental biology, Parasitology, Bone marrow, Immunologic diseases. Allergy, CD8, Cloning, Developmental Biology

الوصف: Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+CCR4+ effector/memory T cells in vivo. However, it remains unknown whether HTLV-1 preferentially infects these T cells or this virus converts infected precursor cells to specialized T cells. Expression of viral genes in vivo is critical to study viral replication and proliferation of infected cells. Therefore, we first analyzed viral gene expression in non-human primates naturally infected with simian T-cell leukemia virus type 1 (STLV-1), whose virological attributes closely resemble those of HTLV-1. Although the tax transcript was detected only in certain tissues, Tax expression was much higher in the bone marrow, indicating the possibility of de novo infection. Furthermore, Tax expression of non-T cells was suspected in bone marrow. These data suggest that HTLV-1 infects hematopoietic cells in the bone marrow. To explore the possibility that HTLV-1 infects hematopoietic stem cells (HSCs), we analyzed integration sites of HTLV-1 provirus in various lineages of hematopoietic cells in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a HTLV-1 carrier using the high-throughput sequencing method. Identical integration sites were detected in neutrophils, monocytes, B cells, CD8+ T cells and CD4+ T cells, indicating that HTLV-1 infects HSCs in vivo. We also detected Tax protein in myeloperoxidase positive neutrophils. Furthermore, dendritic cells differentiated from HTLV-1 infected monocytes caused de novo infection to T cells, indicating that infected monocytes are implicated in viral spreading in vivo. Certain integration sites were re-detected in neutrophils from HAM/TSP patients at different time points, indicating that infected HSCs persist and differentiate in vivo. This study demonstrates that HTLV-1 infects HSCs, and infected stem cells differentiate into diverse cell lineages. These data indicate that infection of HSCs can contribute to the persistence and spread of HTLV-1 in vivo.
Author summary HTLV-1 primarily infects peripheral CD4+CCR4+CADM1+ T cells in vivo. In this study, we show that HTLV-1 infects HSCs, which differentiate into multiple lineages of hematopoietic cells, and likely act as viral reservoir, giving rise to infected neutrophils, monocytes and B cells. Infected monocytes are thought to spread virus in vivo. Infected T cells in the periphery are chimeric in origin: T cells newly infected in the periphery, and infected T cells differentiated from infected HSCs. This observation suggests that viral genes such as HBZ and tax are responsible for converging the molecular differentiation program into a single direction with the characteristic immunophenotype associated with the expression of CCR4 and CADM1. It has been believed that HTLV-1 infects target cells in the periphery. However, this study reveals a new strategy of HTLV-1 spreading in vivo. These findings have implications for understanding of HTLV-1 pathogenesis as well as treatment of HTLV-1 associated diseases.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b78ac0efffc164c2bf10388e31390d0Test
http://hdl.handle.net/2298/41365Test

المؤلفون: Sandra Verónica Gallego, María Celia Frutos, Marcos Balangero, Sebastián Blanco

المصدر: Infection, Genetics and Evolution. 90:104765

مصطلحات موضوعية: Adult, 0301 basic medicine, Microbiology (medical), viruses, Genetic stability, 030106 microbiology, Human T-lymphotropic virus, Microbiology, Genome, Virus, Serology, 03 medical and health sciences, immune system diseases, Genetics, Humans, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Human T-lymphotropic virus 1, Molecular epidemiology, biology, virus diseases, Gene Products, tax, biology.organism_classification, HTLV-I Infections, 030104 developmental biology, Infectious Diseases, Female, Identification (biology)

الوصف: This is the first report of HTLV-1 infection without detectable tax gene. Even though the tax gene of HTLV-1 presents high genetic stability, in the case presented here no sequence of tax was detected by three different and widely used molecular assays targeting several sequences of the gene. Nevertheless, HTLV-1 pol and env genes and LTR region were properly detectable. Several PCRs targeting tax sequences have been developed and largely used for molecular diagnosis of HTLV infection since the tax gene of HTLV-1 is known to be well preserved and intolerant to changes or mutations. In the case reported here, molecular detection of the virus was challenging. HTLV prevalence is complex and in many regions remains unknown. The identification of HTLV-infected individuals is important to determine its actual prevalence and design strategies to reduce viral spread. The finding and communication of HTLV-1 defective-provirus strains is important and necessary to guide the selection of representative target sequences on HTLV genome to design molecular assays, highlighting that different sequences should be combined to ensure adequate diagnosis. The latter is especially relevant in cases when discordant results between serological and molecular assays. This report contributes to the knowledge of the overall molecular epidemiology of HTLV-1 and encourages the need of surveillance of HTLV-1 "missed tax gene profiles" and the evaluation of the impact of these defective viral variants on molecular diagnosis and human health.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f6c55a53fb783e3001859d36a1d59eeTest
https://doi.org/10.1016/j.meegid.2021.104765Test