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Lemos, Marcílio Figueiredo
Moreira, Regina Celia
Texto completo SciELO Brasil
[PMID]:29236927
[Au] Autor:Caterino-de-Araujo A; Alves FA; Campos KR; Lemos MF; Moreira RC
[Ad] Endereço:Centro de Imunologia, Laboratório de Pesquisa em HTLV, Instituto Adolfo Lutz, Secretaria de Estado da Saúde de São Paulo, São Paulo, SP, Brasil.
[Ti] Título:Making the invisible visible: searching for human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) in Brazilian patients with viral hepatitis B and C.
[So] Source:Mem Inst Oswaldo Cruz;113(2):130-134, 2018 Feb.
[Is] ISSN:1678-8060
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:With this study, the authors hope to alert clinicians regarding the presence of human T-cell lymphotropic virus type 1 and 2 (HTLV-1/-2) infections in patients with viral hepatitis B and C in Brazil. HTLV-1/-2 were detected in 1.3% of hepatitis B virus (HBV)- and 5.3% of hepatitis C virus (HCV)-infected blood samples sent for laboratory viral load measurements. A partial association of human immunodeficiency virus (HIV)-1 and HTLV-1/-2 infection was detected in patients with HCV (HIV+, 27.3%), whereas this association was almost 100% in HBV-infected patients (HIV+, all except one). The high prevalence of HTLV-1/-2 infection among patients with hepatitis C was of concern, as HTLV-1/-2 could change the natural course of subsequent liver disease. The authors suggest including HTLV-1/-2 serology in the battery of tests used when following patients with viral hepatitis in Brazil, regardless of the HIV status.
[Mh] Termos MeSH primário: Infecções por HTLV-I/diagnóstico
Infecções por HTLV-II/diagnóstico
Hepatite B/complicações
Hepatite C/complicações
[Mh] Termos MeSH secundário: Brasil/epidemiologia
Infecções por HTLV-I/complicações
Infecções por HTLV-I/epidemiologia
Infecções por HTLV-II/complicações
Infecções por HTLV-II/epidemiologia
Hepatite B/epidemiologia
Hepatite C/epidemiologia
Vírus 1 Linfotrópico T Humano/isolamento & purificação
Vírus 2 Linfotrópico T Humano/isolamento & purificação
Seres Humanos
Notificação Compulsória
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE


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[PMID]:29414279
[Au] Autor:Sato T; Coler-Reilly ALG; Yagishita N; Araya N; Inoue E; Furuta R; Watanabe T; Uchimaru K; Matsuoka M; Matsumoto N; Hasegawa Y; Yamano Y
[Ad] Endereço:From the Department of Rare Diseases Research, Institute of Medical Science (T.S., A.L.G.C.-R., N.Y., N.A., Y.Y.), Medical Informatics (E.I.), and the Departments of Pharmacology (N.M.) and Neurology (Y.H.), St. Marianna University School of Medicine, and the Department of Advanced Medical Innovatio
[Ti] Título:Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy.
[So] Source:N Engl J Med;378(6):529-538, 2018 02 08.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces functional changes, ultimately causing chronic spinal cord inflammation. We evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets infected cells, in patients with HAM-TSP. METHODS: In this uncontrolled, phase 1-2a study, we assessed the safety, pharmacokinetics, and efficacy of mogamulizumab in patients with glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21 patients received a single infusion of mogamulizumab (at doses of 0.003 mg per kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those patients, 19 continued on to the phase 2a study and received infusions, over a period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg per kilogram at 12-week intervals. RESULTS: The side effects of mogamulizumab did not limit administration up to the maximum dose (0.3 mg per kilogram). The most frequent side effects were grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each in 33%). The dose-dependent reduction in the proviral load in peripheral-blood mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI], 51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day 29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI, 10.7 to 31.4] in the neopterin level) was maintained with additional infusions throughout the phase 2a study. A reduction in spasticity was noted in 79% of the patients and a decrease in motor disability in 32%. CONCLUSIONS: Mogamulizumab decreased the number of HTLV-1-infected cells and the levels of inflammatory markers. Rash was the chief side effect. The effect of mogamulizumab on clinical HAM-TSP needs to be clarified in future studies. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .).
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/administração & dosagem
Antineoplásicos/administração & dosagem
Vírus 1 Linfotrópico T Humano/isolamento & purificação
Paraparesia Espástica Tropical/tratamento farmacológico
Receptores CCR4/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adulto
Idoso
Anticorpos Monoclonais Humanizados/efeitos adversos
Anticorpos Monoclonais Humanizados/farmacocinética
Antineoplásicos/efeitos adversos
Antineoplásicos/farmacocinética
Área Sob a Curva
Relação Dose-Resposta a Droga
Esquema de Medicação
Exantema/induzido quimicamente
Feminino
Seres Humanos
Masculino
Meia-Idade
Paraparesia Espástica Tropical/imunologia
Linfócitos T/imunologia
Carga Viral
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents); 0 (Receptors, CCR4); YI437801BE (mogamulizumab)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1704827


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[PMID]:29186194
[Au] Autor:Furuta R; Yasunaga JI; Miura M; Sugata K; Saito A; Akari H; Ueno T; Takenouchi N; Fujisawa JI; Koh KR; Higuchi Y; Mahgoub M; Shimizu M; Matsuda F; Melamed A; Bangham CR; Matsuoka M
[Ad] Endereço:Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
[Ti] Título:Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo.
[So] Source:PLoS Pathog;13(11):e1006722, 2017 Nov.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Infecções por HTLV-I/virologia
Células-Tronco Hematopoéticas/virologia
Vírus 1 Linfotrópico T Humano/fisiologia
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD8-Positivos/virologia
Células Cultivadas
Produtos do Gene tax/genética
Produtos do Gene tax/metabolismo
Infecções por HTLV-I/imunologia
Vírus 1 Linfotrópico T Humano/genética
Seres Humanos
Macaca mulatta
Neutrófilos/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gene Products, tax)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006722


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[PMID]:28742148
[Au] Autor:Groussaud D; Khair M; Tollenaere AI; Waast L; Kuo MS; Mangeney M; Martella C; Fardini Y; Coste S; Souidi M; Benit L; Pique C; Issad T
[Ad] Endereço:INSERM, U1016, Institut Cochin, Paris, France.
[Ti] Título:Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription.
[So] Source:PLoS Pathog;13(7):e1006518, 2017 Jul.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The viral Tax oncoprotein plays a key role in both Human T-cell lymphotropic virus type 1 (HTLV-1)-replication and HTLV-1-associated pathologies, notably adult T-cell leukemia. Tax governs the transcription from the viral 5'LTR, enhancing thereby its own expression, via the recruitment of dimers of phosphorylated CREB to cAMP-response elements located within the U3 region (vCRE). In addition to phosphorylation, CREB is also the target of O-GlcNAcylation, another reversible post-translational modification involved in a wide range of diseases, including cancers. O-GlcNAcylation consists in the addition of O-linked-N-acetylglucosamine (O-GlcNAc) on Serine or Threonine residues, a process controlled by two enzymes: O-GlcNAc transferase (OGT), which transfers O-GlcNAc on proteins, and O-GlcNAcase (OGA), which removes it. In this study, we investigated the status of O-GlcNAcylation enzymes in HTLV-1-transformed T cells. We found that OGA mRNA and protein expression levels are increased in HTLV-1-transformed T cells as compared to control T cell lines while OGT expression is unchanged. However, higher OGA production coincides with a reduction in OGA specific activity, showing that HTLV-1-transformed T cells produce high level of a less active form of OGA. Introducing Tax into HEK-293T cells or Tax-negative HTLV-1-transformed TL-om1 T cells is sufficient to inhibit OGA activity and increase total O-GlcNAcylation, without any change in OGT activity. Furthermore, Tax interacts with the OGT/OGA complex and inhibits the activity of OGT-bound OGA. Pharmacological inhibition of OGA increases CREB O-GlcNAcylation as well as HTLV-1-LTR transactivation by Tax and CREB recruitment to the LTR. Moreover, overexpression of wild-type CREB but not a CREB protein mutated on a previously described O-GlcNAcylation site enhances Tax-mediated LTR transactivation. Finally, both OGT and OGA are recruited to the LTR. These findings reveal the interplay between Tax and the O-GlcNAcylation pathway and identify new key molecular actors involved in the assembly of the Tax-dependent transactivation complex.
[Mh] Termos MeSH primário: Produtos do Gene tax/metabolismo
Infecções por HTLV-I/virologia
Vírus 1 Linfotrópico T Humano/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Linfócitos T/virologia
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
Regulação Viral da Expressão Gênica
Produtos do Gene tax/genética
Infecções por HTLV-I/enzimologia
Infecções por HTLV-I/genética
Infecções por HTLV-I/metabolismo
Interações Hospedeiro-Patógeno
Vírus 1 Linfotrópico T Humano/genética
Seres Humanos
N-Acetilglucosaminiltransferases/genética
Processamento de Proteína Pós-Traducional
Linfócitos T/enzimologia
Linfócitos T/metabolismo
Transcrição Genética
beta-N-Acetil-Hexosaminidases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic AMP Response Element-Binding Protein); 0 (Gene Products, tax); 0 (tax protein, Human T-lymphotrophic virus 1); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (O-GlcNAc transferase); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006518


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[PMID]:28910419
[Au] Autor:Sawada L; Nagano Y; Hasegawa A; Kanai H; Nogami K; Ito S; Sato T; Yamano Y; Tanaka Y; Masuda T; Kannagi M
[Ad] Endereço:Department of Immunotherapeutics, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Bunkyo-ku, Tokyo, Japan.
[Ti] Título:IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways.
[So] Source:PLoS Pathog;13(9):e1006597, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human T-cell leukemia virus type-1 (HTLV-1) causes two distinct diseases, adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since there are no disease-specific differences among HTLV-1 strains, the etiological mechanisms separating these respective lymphoproliferative and inflammatory diseases are not well understood. In this study, by using IL-2-dependent HTLV-1-infected T-cell lines (ILTs) established from patients with ATL and HAM/TSP, we demonstrate that the anti-inflammatory cytokine IL-10 and its downstream signals potentially act as a switch for proliferation in HTLV-1-infected cells. Among six ILTs used, ILTs derived from all three ATL patients grew much faster than those from three HAM/TSP patients. Although most of the ILTs tested produced IFN-γ and IL-6, the production of IL-10 was preferentially observed in the rapid-growing ILTs. Interestingly, treatment with exogenous IL-10 markedly enhanced proliferation of the slow-growing HAM/TSP-derived ILTs. The IL-10-mediated proliferation of these ILTs was associated with phosphorylation of STAT3 and induction of survivin and IRF4, all of which are characteristics of ATL cells. Knockdown of STAT3 reduced expression of IL-10, implying a positive-feedback regulation between STAT3 and IL-10. STAT3 knockdown also reduced survivin and IRF4 in the IL-10- producing or IL-10- treated ILTs. IRF4 knockdown further suppressed survivin expression and the cell growth in these ILTs. These findings indicate that the IL-10-mediated signals promote cell proliferation in HTLV-1-infected cells through the STAT3 and IRF4 pathways. Our results imply that, although HTLV-1 infection alone may not be sufficient for cell proliferation, IL-10 and its signaling pathways within the infected cell itself and/or its surrounding microenvironment may play a critical role in pushing HTLV-1-infected cells towards proliferation at the early stages of HTLV-1 leukemogenesis. This study provides useful information for understanding of disease mechanisms and disease-prophylactic strategies in HTLV-1 infection.
[Mh] Termos MeSH primário: Proliferação Celular/fisiologia
Vírus 1 Linfotrópico T Humano
Interleucina-10/metabolismo
Leucemia-Linfoma de Células T do Adulto/imunologia
Transdução de Sinais
[Mh] Termos MeSH secundário: Citocinas/metabolismo
Seres Humanos
Fatores Reguladores de Interferon/metabolismo
Paraparesia Espástica Tropical/imunologia
Fator de Transcrição STAT3/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (IL10 protein, human); 0 (Interferon Regulatory Factors); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 0 (interferon regulatory factor-4); 130068-27-8 (Interleukin-10)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006597


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[PMID]:28866351
[Au] Autor:Sakihama S; Saito M; Kuba-Miyara M; Tomoyose T; Taira N; Miyagi T; Hayashi M; Kinjo S; Nakachi S; Tedokon I; Nishi Y; Tamaki K; Morichika K; Uchihara JN; Morishima S; Karube KN; Tanaka Y; Masuzaki H; Fukushima T
[Ad] Endereço:Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara, Japan.
[Ti] Título:Human T-cell leukemia virus type I Tax genotype analysis in Okinawa, the southernmost and remotest islands of Japan: Different distributions compared with mainland Japan and the potential value for the prognosis of aggressive adult T-cell leukemia/lymphoma.
[So] Source:Leuk Res;61:18-24, 2017 Oct.
[Is] ISSN:1873-5835
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution-60 (44%) taxA cases and 76 (56%) taxB cases-differed from that of a previous report from Kagoshima Prefecture in mainland Japan (taxA, 10%; taxB, 90%). A comparison of the clinical outcomes of 45 patients (taxA, 14; taxB, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for taxA (50% and 35%, respectively) were lower than those for taxB (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of taxA compared with taxB was 2.68 (95% confidence interval, 0.87-8.25; P=0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL.
[Mh] Termos MeSH primário: Produtos do Gene tax/genética
Infecções por HTLV-I/patologia
Leucemia-Linfoma de Células T do Adulto/patologia
Leucemia-Linfoma de Células T do Adulto/virologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Feminino
Genótipo
Infecções por HTLV-I/tratamento farmacológico
Infecções por HTLV-I/mortalidade
Vírus 1 Linfotrópico T Humano/genética
Seres Humanos
Japão
Estimativa de Kaplan-Meier
Leucemia-Linfoma de Células T do Adulto/mortalidade
Masculino
Meia-Idade
Reação em Cadeia da Polimerase
Polimorfismo de Fragmento de Restrição
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gene Products, tax); 0 (tax protein, Human T-lymphotrophic virus 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170904
[St] Status:MEDLINE


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[PMID]:28821586
[Au] Autor:Wang J; Kang L; Song D; Liu L; Yang S; Ma L; Guo Z; Ding H; Wang H; Yang B
[Ad] Endereço:Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, China.
[Ti] Título:Ku70 Senses HTLV-1 DNA and Modulates HTLV-1 Replication.
[So] Source:J Immunol;199(7):2475-2482, 2017 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human T lymphotropic virus type 1 (HTLV-1) belongs to the deltaretrovirus family and has been linked to multiple diseases. However, the innate host defense against HTLV-1 is unclear. In this study, we report that the expression of Ku70, a known DNA sensor against DNA viruses, could be induced by HTLV-1 infection in HeLa, PMA-differentiated THP1 cells, primary human monocytes, and human monocyte-derived macrophages. In these cells, the overexpression of Ku70 inhibited the HTLV-1 protein expression, whereas the knockdown of Ku70 promoted the HTLV-1 protein expression. Furthermore, the overexpression of Ku70 enhanced the cellular response to HTLV-1 infection, whereas Ku70 knockdown yielded the opposite effect. Additionally, Ku70 was found to interact with HTLV-1 reverse transcription intermediate ssDNA90. ssDNA90 stimulation induced Ku70 expression and Ku70 promoted ssDNA90-triggered innate immune responses. Finally, HTLV-1 infection enhanced the association between Ku70 and stimulator of IFN genes, suggesting that stimulator of IFN genes was involved in Ku70-mediated host defenses against HTLV-1 infection. Taken together, our findings suggest a new sensor that detects HTLV-1 reverse transcription intermediate and controls HTLV-1 replication. These findings may provide new angles to understand host defenses against HTLV-1 infection and HTLV-1-associated diseases.
[Mh] Termos MeSH primário: DNA Viral
Vírus 1 Linfotrópico T Humano/fisiologia
Autoantígeno Ku/genética
Autoantígeno Ku/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Células Cultivadas
Produtos do Gene tax/genética
Células HeLa
Vírus 1 Linfotrópico T Humano/genética
Vírus 1 Linfotrópico T Humano/imunologia
Seres Humanos
Imunidade Inata
Interferons/genética
Interferons/imunologia
Autoantígeno Ku/deficiência
Autoantígeno Ku/imunologia
Macrófagos/virologia
Monócitos/virologia
Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Viral); 0 (Gene Products, tax); 0 (gag Gene Products, Human Immunodeficiency Virus); 0 (p19 protein, Human T-lymphotropic virus 1); 9008-11-1 (Interferons); EC 4.2.99.- (Ku Autoantigen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700111


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[PMID]:28768861
[Au] Autor:Narulla MS; Alsairi A; Charmier L; Noonan S; Conroy D; Hall WW; Sheehy N
[Ad] Endereço:Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
[Ti] Título:Positive and Negative Regulation of Type I Interferons by the Human T Cell Leukemia Virus Antisense Protein HBZ.
[So] Source:J Virol;91(20), 2017 Oct 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The pathogenesis of human T cell leukemia virus type 1 (HTLV-1) is strongly linked to the viral regulatory proteins Tax1 and HBZ, whose opposing functions contribute to the clinical outcome of infection. Type I interferons alpha and beta (IFN-α and IFN-ß) are key cytokines involved in innate immunity, and IFN-α, in combination with other antivirals, is extensively used in the treatment of HTLV-1 infection. The relationship between HTLV-1 and IFN signaling is unclear, and to date the effect of HBZ on this pathway has not been examined. Here we report that HBZ significantly enhances interferon regulatory factor 7 (IRF7)-induced IFN-α- and IFN-stimulated response element (ISRE) promoter activities and IFN-α production and can counteract the inhibitory effect of Tax1. In contrast to this, we show that HBZ and Tax1 cooperate to inhibit the induction of IFN-ß and ISRE promoters by IRF3 and IFN-ß production. In addition, we reveal that HBZ enhances ISRE activation by IFN-α. We further show that HBZ enhances IRF7 and suppresses IRF3 activation by TBK1 and IKKε. We demonstrate that HBZ has no effect on virus-induced nuclear accumulation of IRF3, suggesting that it may inhibit IRF3 activity at a transcriptional level. We show that HBZ physically interacts with IRF7 and IKKε but not with IRF3 or TBK1. Overall, our findings suggest that both HBZ and Tax1 are negative regulators of immediate early IFN-ß innate immune responses, while HBZ but not Tax1 positively regulates the induction of IFN-α and downstream IFN-α signaling. Type I interferons are powerful antiviral cytokines and are used extensively in the treatment of HTLV-1-induced adult T cell leukemia (ATL). To date, the relationship between HTLV-1 and the IFN pathway is poorly understood, and studies so far have focused on Tax1. Our study is unique in that it examined the effect of HBZ, alone or in combination with Tax1, on type I IFN signaling. This is important because HBZ is frequently the only viral protein expressed in infected cells, particularly at later stages of infection. A better understanding of the how HBZ regulates IFN signaling may lead to the development of therapeutics that can modify such responses and improve the clinical outcome for infected individuals.
[Mh] Termos MeSH primário: Fatores de Transcrição de Zíper de Leucina Básica/metabolismo
Interações Hospedeiro-Patógeno
Vírus 1 Linfotrópico T Humano/metabolismo
Interferon-alfa/metabolismo
Interferon beta/metabolismo
Proteínas dos Retroviridae/metabolismo
[Mh] Termos MeSH secundário: Antivirais/imunologia
Antivirais/metabolismo
Linhagem Celular
Seres Humanos
Quinase I-kappa B/metabolismo
Imunidade Inata
Fator Regulador 3 de Interferon/metabolismo
Fator Regulador 7 de Interferon/metabolismo
Interferon-alfa/imunologia
Interferon beta/imunologia
Regiões Promotoras Genéticas
Proteínas Serina-Treonina Quinases/metabolismo
Elementos de Resposta
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Basic-Leucine Zipper Transcription Factors); 0 (HBZ protein, human T-cell leukemia virus type I); 0 (IRF3 protein, human); 0 (Interferon Regulatory Factor-3); 0 (Interferon Regulatory Factor-7); 0 (Interferon-alpha); 0 (Retroviridae Proteins); 77238-31-4 (Interferon-beta); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); EC 2.7.11.10 (I-kappa B Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE


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[PMID]:28724766
[Au] Autor:Ishihara Y; Tanaka Y; Kobayashi S; Kawamura K; Nakasone H; Gomyo A; Hayakawa J; Tamaki M; Akahoshi Y; Harada N; Kusuda M; Kameda K; Ugai T; Wada H; Sakamoto K; Sato M; Terasako-Saito K; Kikuchi M; Kimura SI; Tanihara A; Kako S; Uchimaru K; Kanda Y
[Ad] Endereço:Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
[Ti] Título:A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax -Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients.
[So] Source:J Virol;91(19), 2017 Oct 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax -specific CD8 cytotoxic T cells (Tax -CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02 ) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax -CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-ß chain of Tax -CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax -CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax -CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax -CTLs, 1,458 Tax -CTLs and 140 clones were identified in this cohort. Tax -CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-ß CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02 HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR CTL response in the progression from carrier state to ATL. ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8 CTLs. In our previous evaluation of Tax -CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-ß chain of Tax -CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR Tax -CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax -CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax -CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-ß CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.
[Mh] Termos MeSH primário: Produtos do Gene tax/imunologia
Antígeno HLA-A24/imunologia
Vírus 1 Linfotrópico T Humano/imunologia
Leucemia-Linfoma de Células T do Adulto/imunologia
Receptores de Antígenos de Linfócitos T/imunologia
Linfócitos T Citotóxicos/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos/genética
Antígenos CD7/metabolismo
Molécula 1 de Adesão Celular
Moléculas de Adesão Celular/metabolismo
Células Cultivadas
Produtos do Gene tax/genética
Antígeno HLA-A24/genética
Infecções por HTLV-I/patologia
Infecções por HTLV-I/virologia
Vírus 1 Linfotrópico T Humano/genética
Seres Humanos
Imunoglobulinas/metabolismo
Memória Imunológica/imunologia
Leucemia-Linfoma de Células T do Adulto/genética
Receptores de Antígenos de Linfócitos T/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD7); 0 (CADM1 protein, human); 0 (Cell Adhesion Molecule-1); 0 (Cell Adhesion Molecules); 0 (Gene Products, tax); 0 (HLA-A24 Antigen); 0 (Immunoglobulins); 0 (Receptors, Antigen, T-Cell); 0 (tax protein, Human T-lymphotrophic virus 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE


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[PMID]:28669733
[Au] Autor:Permatasari HK; Nakahata S; Ichikawa T; Morishita K
[Ad] Endereço:Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
[Ti] Título:BCL11B is frequently downregulated in HTLV-1-infected T-cells through Tax-mediated proteasomal degradation.
[So] Source:Biochem Biophys Res Commun;490(3):1086-1092, 2017 Aug 26.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia-lymphoma (ATLL). The HTLV-1-encoded protein Tax plays important roles in the proliferation of HTLV-1-infected T-cells by affecting cellular proteins. In this study, we showed that Tax transcriptionally and post-transcriptionally downregulates the expression of the tumor suppressor gene B-cell leukemia/lymphoma 11B (BCL11B), which encodes a lymphoid-related transcription factor. BCL11B expression was downregulated in HTLV-1-infected T-cell lines at the mRNA and protein levels, and forced expression of BCL11B suppressed the proliferation of these cells. The proteasomal inhibitor MG132 increased BCL11B expression in HTLV-1-infected cell lines, and colocalization of Tax with BCL11B was detected in the cytoplasm of HTLV-1-infected T-cells following MG132 treatment. shRNA knock-down of Tax expression also increased the expression of BCL11B in HTLV-1-infected cells. Moreover, we found that Tax physically binds to BCL11B protein and induces the polyubiquitination of BCL11B and proteasome-dependent degradation of BCL11B. Thus, inactivation of BCL11B by Tax protein may play an important role in the Tax-mediated leukemogenesis.
[Mh] Termos MeSH primário: Produtos do Gene tax/metabolismo
Infecções por HTLV-I/metabolismo
Vírus 1 Linfotrópico T Humano/fisiologia
Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Proteínas Repressoras/metabolismo
Proteínas Supressoras de Tumor/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Regulação para Baixo
Infecções por HTLV-I/genética
Infecções por HTLV-I/virologia
Seres Humanos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
Leucemia-Linfoma Linfoblástico de Células T Precursoras/virologia
Proteólise
Proteínas Repressoras/genética
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL11B protein, human); 0 (Gene Products, tax); 0 (Repressor Proteins); 0 (Tumor Suppressor Proteins); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE



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