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  1 / 16818 MEDLINE  
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[PMID]:28454901
[Au] Autor:Wu S; Han J; Zhang X; Zhong D; Liu R
[Ad] Endereço:School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China.
[Ti] Título:A computational model for predicting integrase catalytic domain of retrovirus.
[So] Source:J Theor Biol;423:63-70, 2017 Jun 21.
[Is] ISSN:1095-8541
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Integrase catalytic domain (ICD) is an essential part in the retrovirus for integration reaction, which enables its newly synthesized DNA to be incorporated into the DNA of infected cells. Owing to the crucial role of ICD for the retroviral replication and the absence of an equivalent of integrase in host cells, it is comprehensible that ICD is a promising drug target for therapeutic intervention. However, annotated ICDs in UniProtKB database have still been insufficient for a good understanding of their statistical characteristics so far. Accordingly, it is of great importance to put forward a computational ICD model in this work to annotate these domains in the retroviruses. The proposed model then discovered 11,660 new putative ICDs after scanning sequences without ICD annotations. Subsequently in order to provide much confidence in ICD prediction, it was tested under different cross-validation methods, compared with other database search tools, and verified on independent datasets. Furthermore, an evolutionary analysis performed on the annotated ICDs of retroviruses revealed a tight connection between ICD and retroviral classification. All the datasets involved in this paper and the application software tool of this model can be available for free download at https://sourceforge.net/projects/icdtool/files/?source=navbar.
[Mh] Termos MeSH primário: Domínio Catalítico
Biologia Computacional
Evolução Molecular
Integrases/química
Retroviridae/classificação
Análise de Sequência de Proteína
[Mh] Termos MeSH secundário: Simulação por Computador
Bases de Dados de Proteínas
Anotação de Sequência Molecular
Software
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.- (Integrases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


  2 / 16818 MEDLINE  
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[PMID]:29304082
[Au] Autor:Gadek KE; Wang H; Hall MN; Sungello M; Libby A; MacLaskey D; Eckel RH; Olwin BB
[Ad] Endereço:Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, Colorado United States of America.
[Ti] Título:Striated muscle gene therapy for the treatment of lipoprotein lipase deficiency.
[So] Source:PLoS One;13(1):e0190963, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Excessive circulating triglycerides due to reduction or loss of lipoprotein lipase activity contribute to hypertriglyceridemia and increased risk for pancreatitis. The only gene therapy treatment for lipoprotein lipase deficiency decreases pancreatitis but minimally reduces hypertriglyceridemia. Synthesized in multiple tissues including striated muscle and adipose tissue, lipoprotein lipase is trafficked to blood vessel endothelial cells where it is anchored at the plasma membrane and hydrolyzes triglycerides into free fatty acids. We conditionally knocked out lipoprotein lipase in differentiated striated muscle tissue lowering striated muscle lipoprotein lipase activity causing hypertriglyceridemia. We then crossed lipoprotein lipase striated muscle knockout mice with mice possessing a conditional avian retroviral receptor gene and injected mice with either a human lipoprotein lipase retrovirus or an mCherry control retrovirus. Post-heparin plasma lipoprotein lipase activity increased for three weeks following human lipoprotein lipase retroviral infection compared to mCherry infected mice. Human lipoprotein lipase infected mice had significantly lower blood triglycerides compared to mCherry controls and were comparable to wild-type blood triglyceride levels. Thus, targeted delivery of human lipoprotein lipase into striated muscle tissue identifies a potential therapeutic target for lipoprotein lipase deficiency.
[Mh] Termos MeSH primário: Terapia Genética
Lipase Lipoproteica/genética
Músculo Estriado/patologia
[Mh] Termos MeSH secundário: Animais
Vetores Genéticos
Seres Humanos
Hipertrigliceridemia/etiologia
Camundongos
Camundongos Knockout
Músculo Estriado/enzimologia
Retroviridae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.1.1.34 (Lipoprotein Lipase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190963


  3 / 16818 MEDLINE  
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[PMID]:28456379
[Au] Autor:Rivière I; Sadelain M
[Ad] Endereço:Center for Cell Engineering, Molecular Pharmacology and Immunology Programs, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
[Ti] Título:Chimeric Antigen Receptors: A Cell and Gene Therapy Perspective.
[So] Source:Mol Ther;25(5):1117-1124, 2017 May 03.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens. The targeting of CD19, a cell surface molecule expressed in the vast majority of leukemias and lymphomas, has been successfully translated in the clinic, earning CAR therapy a special distinction in the selection of "cancer immunotherapy" by Science as the breakthrough of the year in 2013. CD19 CAR therapy is predicated on advances in genetic engineering, T cell biology, tumor immunology, synthetic biology, target identification, cell manufacturing sciences, and regulatory compliance-the central tenets of CAR therapy. Here, we review two of these foundations: the genetic engineering approaches and cell types to engineer.
[Mh] Termos MeSH primário: Antígenos CD19/genética
Terapia Baseada em Transplante de Células e Tecidos/métodos
Leucemia/terapia
Linfoma/terapia
Proteínas Mutantes Quiméricas/genética
Receptores de Antígenos de Linfócitos T/genética
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Antígenos CD19/imunologia
Engenharia Celular/métodos
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/imunologia
Seres Humanos
Imunoterapia/métodos
Lentivirus/genética
Lentivirus/imunologia
Leucemia/genética
Leucemia/imunologia
Leucemia/patologia
Linfoma/genética
Linfoma/imunologia
Linfoma/patologia
Proteínas Mutantes Quiméricas/imunologia
Engenharia de Proteínas/métodos
Receptores de Antígenos de Linfócitos T/imunologia
Retroviridae/genética
Retroviridae/imunologia
Linfócitos T/classificação
Linfócitos T/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antigens, CD19); 0 (CD19 molecule, human); 0 (Mutant Chimeric Proteins); 0 (Receptors, Antigen, T-Cell)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


  4 / 16818 MEDLINE  
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[PMID]:29232693
[Au] Autor:Rai SK; Sangesland M; Lee M; Esnault C; Cui Y; Chatterjee AG; Levin HL
[Ad] Endereço:Section on Eukaryotic Transposable Elements, Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
[Ti] Título:Host factors that promote retrotransposon integration are similar in distantly related eukaryotes.
[So] Source:PLoS Genet;13(12):e1006775, 2017 12.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Retroviruses and Long Terminal Repeat (LTR)-retrotransposons have distinct patterns of integration sites. The oncogenic potential of retrovirus-based vectors used in gene therapy is dependent on the selection of integration sites associated with promoters. The LTR-retrotransposon Tf1 of Schizosaccharomyces pombe is studied as a model for oncogenic retroviruses because it integrates into the promoters of stress response genes. Although integrases (INs) encoded by retroviruses and LTR-retrotransposons are responsible for catalyzing the insertion of cDNA into the host genome, it is thought that distinct host factors are required for the efficiency and specificity of integration. We tested this hypothesis with a genome-wide screen of host factors that promote Tf1 integration. By combining an assay for transposition with a genetic assay that measures cDNA recombination we could identify factors that contribute differentially to integration. We utilized this assay to test a collection of 3,004 S. pombe strains with single gene deletions. Using these screens and immunoblot measures of Tf1 proteins, we identified a total of 61 genes that promote integration. The candidate integration factors participate in a range of processes including nuclear transport, transcription, mRNA processing, vesicle transport, chromatin structure and DNA repair. Two candidates, Rhp18 and the NineTeen complex were tested in two-hybrid assays and were found to interact with Tf1 IN. Surprisingly, a number of pathways we identified were found previously to promote integration of the LTR-retrotransposons Ty1 and Ty3 in Saccharomyces cerevisiae, indicating the contribution of host factors to integration are common in distantly related organisms. The DNA repair factors are of particular interest because they may identify the pathways that repair the single stranded gaps flanking the sites of strand transfer following integration of LTR retroelements.
[Mh] Termos MeSH primário: Fatores Hospedeiros de Integração/genética
Recombinação Genética
Retroelementos/genética
Sequências Repetidas Terminais/genética
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Reparo do DNA/genética
Eucariotos/genética
Regulação Fúngica da Expressão Gênica
Integrases/genética
Regiões Promotoras Genéticas
DNA Polimerase Dirigida por RNA/genética
Retroviridae/genética
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Schizosaccharomyces/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Integration Host Factors); 0 (Retroelements); 0 (Saccharomyces cerevisiae Proteins); 0 (Spp382 protein, S cerevisiae); EC 2.3.2.27 (Rhp18 protein, S pombe); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.7.- (Integrases); EC 2.7.7.49 (RNA-Directed DNA Polymerase); EC 2.7.7.49 (reverse transcriptase Ty3, S cerevisiae)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180111
[Lr] Data última revisão:
180111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006775


  5 / 16818 MEDLINE  
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[PMID]:29054407
[Au] Autor:Wang Z; Hou X; Wang Y; Xu A; Cao W; Liao M; Zhang R; Tang J
[Ad] Endereço:College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China.
[Ti] Título:Ubiquitination of non-lysine residues in the retroviral integrase.
[So] Source:Biochem Biophys Res Commun;494(1-2):57-62, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Retroviral integrase catalyzes the integration of retroviral genome into host chromosomal DNA, which is a prerequisite of effective viral replication and infection. The human immunodeficiency virus type 1 (HIV-1) integrase has previously been reported to be regulated by the ubiquitination, but the molecular characterization of integrase ubiquitination is still unclear. In this study, we analyzed the ubiquitination of avian leukosis virus (ALV) integrase in detail. The ubiquitination assay showed that, like HIV-1, ALV integrase could also be modified by ubiquitination when expressed in 293 T and DF-1 cells. Domain mapping analysis revealed that the ubiquitination of ALV integrase might mainly occurred in the catalytic core and the N-terminal zinc-binding domains. Both lysine and non-lysine residues within integrase of ALV and HIV-1 were responsible for the ubiquitin conjugation, and the N-terminal HHCC zinc-binding motif might play an important role in mediating integrase ubiquitination. Interestingly, mass spectrometry analysis identified the Thr10 and Cys37 residues in the HHCC zinc-binding motif as the ubiquitination sites, indicating that ubiquitin may be conjugated to ALV integrase through direct interaction with the non-lysine residues. These findings revealed the detailed features of retroviral integrase ubiquitination and found a novel mechanism of ubiquitination mediated by the non-lysine residues within the N-terminal zinc-binding domain of integrase.
[Mh] Termos MeSH primário: Vírus da Leucose Aviária/enzimologia
Integrase de HIV/química
Integrase de HIV/metabolismo
Integrases/química
Integrases/metabolismo
Proteínas dos Retroviridae/química
Proteínas dos Retroviridae/metabolismo
Retroviridae/enzimologia
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sequência de Aminoácidos
Animais
Vírus da Leucose Aviária/genética
Vírus da Leucose Aviária/fisiologia
Linhagem Celular
Galinhas
Células HEK293
Integrase de HIV/genética
HIV-1/enzimologia
HIV-1/genética
HIV-1/fisiologia
Seres Humanos
Integrases/genética
Lisina/química
Mutagênese Sítio-Dirigida
Retroviridae/genética
Retroviridae/fisiologia
Proteínas dos Retroviridae/genética
Ubiquitinação
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Retroviridae Proteins); 0 (p31 integrase protein, Human immunodeficiency virus 1); EC 2.7.7.- (HIV Integrase); EC 2.7.7.- (Integrases); J41CSQ7QDS (Zinc); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171022
[St] Status:MEDLINE


  6 / 16818 MEDLINE  
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[PMID]:29040325
[Au] Autor:Roganowicz MD; Komurlu S; Mukherjee S; Plewka J; Alam SL; Skorupka KA; Wan Y; Dawidowski D; Cafiso DS; Ganser-Pornillos BK; Campbell EM; Pornillos O
[Ad] Endereço:Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
[Ti] Título:TRIM5α SPRY/coiled-coil interactions optimize avid retroviral capsid recognition.
[So] Source:PLoS Pathog;13(10):e1006686, 2017 Oct.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Restriction factors are important components of intrinsic cellular defense mechanisms against viral pathogens. TRIM5α is a restriction factor that intercepts the incoming capsid cores of retroviruses such as HIV and provides an effective species-specific barrier to retroviral infection. The TRIM5α SPRY domain directly binds the capsid with only very weak, millimolar-level affinity, and productive capsid recognition therefore requires both TRIM5α dimerization and assembly of the dimers into a multivalent hexagonal lattice to promote avid binding. Here, we explore the important unresolved question of whether the SPRY domains are flexibly linked to the TRIM lattice or more precisely positioned to maximize avidity. Biochemical and biophysical experiments indicate that the linker segment connecting the SPRY domain to the coiled-coil domain adopts an α-helical fold, and that this helical portion mediates interactions between the two domains. Targeted mutations were generated to disrupt the putative packing interface without affecting dimerization or higher-order assembly, and we identified mutant proteins that were nevertheless deficient in capsid binding in vitro and restriction activity in cells. Our studies therefore support a model wherein substantial avidity gains during assembly-mediated capsid recognition by TRIM5α come in part from tailored spacing of tethered recognition domains.
[Mh] Termos MeSH primário: Capsídeo/imunologia
Proteínas de Transporte/química
Proteínas de Transporte/imunologia
Retroviridae/imunologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Modelos Moleculares
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (TRIM5 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171018
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006686


  7 / 16818 MEDLINE  
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[PMID]:28957413
[Au] Autor:Markussen LK; Isidor MS; Breining P; Andersen ES; Rasmussen NE; Petersen LI; Pedersen SB; Richelsen B; Hansen JB
[Ad] Endereço:Department of Biology, University of Copenhagen, Copenhagen, Denmark.
[Ti] Título:Characterization of immortalized human brown and white pre-adipocyte cell models from a single donor.
[So] Source:PLoS One;12(9):e0185624, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Brown adipose tissue with its constituent brown adipocytes is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. The molecular control of brown adipocyte differentiation and function has been extensively studied in mice, but relatively little is known about such regulatory mechanisms in humans, which in part is due to lack of human brown adipose tissue derived cell models. Here, we used retrovirus-mediated overexpression to stably integrate human telomerase reverse transcriptase (TERT) into stromal-vascular cell fractions from deep and superficial human neck adipose tissue biopsies from the same donor. The brown and white pre-adipocyte cell models (TERT-hBA and TERT-hWA, respectively) displayed a stable proliferation rate and differentiation until at least passage 20. Mature TERT-hBA adipocytes expressed higher levels of thermogenic marker genes and displayed a higher maximal respiratory capacity than mature TERT-hWA adipocytes. TERT-hBA adipocytes were UCP1-positive and responded to ß-adrenergic stimulation by activating the PKA-MKK3/6-p38 MAPK signaling module and increasing thermogenic gene expression and oxygen consumption. Mature TERT-hWA adipocytes underwent efficient rosiglitazone-induced 'browning', as demonstrated by strongly increased expression of UCP1 and other brown adipocyte-enriched genes. In summary, the TERT-hBA and TERT-hWA cell models represent useful tools to obtain a better understanding of the molecular control of human brown and white adipocyte differentiation and function as well as of browning of human white adipocytes.
[Mh] Termos MeSH primário: Adipócitos/citologia
Tecido Adiposo Marrom/citologia
Tecido Adiposo Branco/citologia
Doadores de Tecidos
[Mh] Termos MeSH secundário: Adipócitos/efeitos dos fármacos
Biópsia
Linhagem Celular Transformada
Colforsina/farmacologia
Seres Humanos
Isoproterenol/farmacologia
Pescoço
Retroviridae/genética
Telomerase/genética
Termogênese
Tiazolidinedionas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Thiazolidinediones); 05V02F2KDG (rosiglitazone); 1F7A44V6OU (Colforsin); EC 2.7.7.49 (Telomerase); L628TT009W (Isoproterenol)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185624


  8 / 16818 MEDLINE  
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[PMID]:28858287
[Au] Autor:Kurachi M; Kurachi J; Chen Z; Johnson J; Khan O; Bengsch B; Stelekati E; Attanasio J; McLane LM; Tomura M; Ueha S; Wherry EJ
[Ad] Endereço:Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
[Ti] Título:Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function.
[So] Source:Nat Protoc;12(9):1980-1998, 2017 Sep.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro-generated effector CD8 T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo. Here, we describe an optimized mouse CD8 T-cell RV transduction protocol that uses simple and rapid Percoll density centrifugation to enrich RV-susceptible activated CD8 T cells. Percoll density centrifugation is simple, can be done on the day of transduction, requires minimal time, has low reagent costs and improves cell recovery (up to 60%), as well as the frequency of RV-transduced cells (∼sixfold over several weeks in vivo as compared with traditional methods). We have used this protocol to assess the long-term stability of CD8 T cells after RV transduction by comparing the durability of T cells transduced with retroviruses expressing each of six commonly used RV reporter genes. Thus, we provide an optimized enrichment and transduction approach that allows long-term in vivo assessment of RV-transduced T cells. The overall procedure from T-cell isolation to RV transduction takes 2 d, and enrichment of activated T cells can be done in 1 h.
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/virologia
Vetores Genéticos/genética
Retroviridae/genética
Transdução Genética/métodos
[Mh] Termos MeSH secundário: Animais
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2017.083


  9 / 16818 MEDLINE  
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[PMID]:28802832
[Au] Autor:Streltsova MA; Barsov E; Erokhina SA; Kovalenko EI
[Ad] Endereço:Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, Moscow 117997, Russia. Electronic address: mstreltsova@mail.ru.
[Ti] Título:Retroviral gene transfer into primary human NK cells activated by IL-2 and K562 feeder cells expressing membrane-bound IL-21.
[So] Source:J Immunol Methods;450:90-94, 2017 Nov.
[Is] ISSN:1872-7905
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Natural killer (NK) cells are capable of rapidly recognizing and efficiently killing tumor cells. This makes them a potentially promising agent for cancer immunotherapy. Additional genetic modifications of NK cells may further improve their anti-tumor efficacy. Numerous technical challenges associated with gene delivery into NK cells have significantly tempered this approach. We achieved efficient retroviral vector transduction of primary human NK cells that were stimulated by a combination of IL-2 and engineered K562 cells expressing membrane-bound IL-21. The activated NK cells were in less differentiated state and expressed NK cell activation receptors NKG2D, NKp30, CD16, and were highly HLA-DR-positive. This NK cell population was highly susceptible to the transduction by both GFP- and NGFR-expressing retroviral vectors, with transduction efficiency exceeding 50%. More mature CD57 NK cell population was generally resistant to retroviral vector transduction because of poor response to the stimulation. Our findings may facilitate retroviral vector-mediated genetic engineering of human primary NK cells for future immunotherapies.
[Mh] Termos MeSH primário: Vetores Genéticos
Imunoterapia/métodos
Interleucina-2/metabolismo
Interleucinas/metabolismo
Células Matadoras Naturais/metabolismo
Leucemia Eritroblástica Aguda/terapia
Ativação Linfocitária
Retroviridae/genética
Transdução Genética
Transfecção/métodos
[Mh] Termos MeSH secundário: Antígenos CD57/imunologia
Antígenos CD57/metabolismo
Diferenciação Celular
Técnicas de Cocultura
Células Alimentadoras
Proteínas Ligadas por GPI/imunologia
Proteínas Ligadas por GPI/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Antígenos HLA-DR/imunologia
Antígenos HLA-DR/metabolismo
Seres Humanos
Interleucina-2/imunologia
Interleucinas/imunologia
Células Jurkat
Células K562
Células Matadoras Naturais/imunologia
Leucemia Eritroblástica Aguda/genética
Leucemia Eritroblástica Aguda/imunologia
Leucemia Eritroblástica Aguda/metabolismo
Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia
Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo
Receptor 3 Desencadeador da Citotoxicidade Natural/imunologia
Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Receptores de IgG/imunologia
Receptores de IgG/metabolismo
Receptores de Fator de Crescimento Neural/genética
Receptores de Fator de Crescimento Neural/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD57 Antigens); 0 (FCGR3B protein, human); 0 (GPI-Linked Proteins); 0 (HLA-DR Antigens); 0 (Interleukin-2); 0 (Interleukins); 0 (KLRK1 protein, human); 0 (NCR3 protein, human); 0 (NGFR protein, human); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (Natural Cytotoxicity Triggering Receptor 3); 0 (Nerve Tissue Proteins); 0 (Receptors, IgG); 0 (Receptors, Nerve Growth Factor); 0 (interleukin-21); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170814
[St] Status:MEDLINE


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[PMID]:28768877
[Au] Autor:Schöne D; Hrycak CP; Windmann S; Lapuente D; Dittmer U; Tenbusch M; Bayer W
[Ad] Endereço:Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
[Ti] Título:Immunodominance of Adenovirus-Derived CD8 T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization.
[So] Source:J Virol;91(20), 2017 Oct 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenovirus (Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8 T cell responses to the encoded transgene. Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8 T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL We show now that induction of GagL -specific CD8 T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL and the two Ad-derived epitopes DNA-binding protein (DBP ) and hexon , we confirmed that Ad epitopes prevent induction of GagL -specific CD8 T cells. Interestingly, while DBP did not interfere with GagL -specific CD8 T cell induction, the H-2D -restricted hexon suppressed the CD8 T cell response to the H-2D -restricted GagL strongly in H-2 mice but not in H-2 mice. This finding indicates that competition occurs at the level of responding CD8 T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL -specific CD8 T cell responses to epitope strings in the presence of hexon IL-2 codelivery did not restore GagL responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses. Ad-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus, , or Preexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.
[Mh] Termos MeSH primário: Adenoviridae/genética
Linfócitos T CD8-Positivos/imunologia
Epitopos de Linfócito T/imunologia
Epitopos Imunodominantes/imunologia
Transgenes
[Mh] Termos MeSH secundário: Adenoviridae/imunologia
Vacinas contra Adenovirus/imunologia
Animais
Linfócitos T CD8-Positivos/química
Vírus da Leucemia Murina de Friend/genética
Vírus da Leucemia Murina de Friend/imunologia
Vetores Genéticos
Imunização
Interleucina-2/administração & dosagem
Interleucina-2/genética
Interleucina-2/imunologia
Ativação Linfocitária
Camundongos
Retroviridae/genética
Retroviridae/imunologia
Vacinas de DNA/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenovirus Vaccines); 0 (Epitopes, T-Lymphocyte); 0 (Immunodominant Epitopes); 0 (Interleukin-2); 0 (Vaccines, DNA)
[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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