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[PMID]:28153748
[Au] Autor:Hammond JA; Lamichhane R; Millar DP; Williamson JR
[Ad] Endereço:Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
[Ti] Título:A DEAD-Box Helicase Mediates an RNA Structural Transition in the HIV-1 Rev Response Element.
[So] Source:J Mol Biol;429(5):697-714, 2017 Mar 10.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nuclear export of partially spliced or unspliced HIV-1 RNA transcripts requires binding of the viral protein regulator of expression of virion (Rev) to the Rev response element (RRE) and subsequent oligomerization in a cooperative manner. Cellular DEAD-box helicase DEAD-box protein 1 (DDX1) plays a role in HIV replication, interacting with and affecting Rev-containing HIV transcripts in vivo, interacting directly with the RRE and Rev in vitro, and promoting Rev oligomerization in vitro. Binding of DDX1 results in enhancement of Rev oligomerization on the RRE that is correlated with an RNA structural change within the RRE that persists even after dissociation of DDX1. Furthermore, this structural transition is likely located within the three-way junction of stem II of the RRE that is responsible for initial Rev binding. This discovery of the stem II structural transition leads to a model wherein DDX1 can act as an RNA chaperone, folding stem IIB into a proper Rev binding conformation.
[Mh] Termos MeSH primário: RNA Helicases DEAD-box/metabolismo
Regulação Viral da Expressão Gênica
HIV-1/genética
RNA Viral/química
Elementos de Resposta
Produtos do Gene rev do Vírus da Imunodeficiência Humana/química
[Mh] Termos MeSH secundário: RNA Helicases DEAD-box/genética
DNA Helicases/metabolismo
HIV-1/fisiologia
Conformação de Ácido Nucleico
Processamento de RNA
Replicação Viral
Produtos do Gene rev do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Viral); 0 (rev Gene Products, Human Immunodeficiency Virus); EC 3.6.4.- (DNA Helicases); EC 3.6.4.13 (DEAD-box RNA Helicases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE


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[PMID]:28122580
[Au] Autor:Balachandran A; Wong R; Stoilov P; Pan S; Blencowe B; Cheung P; Harrigan PR; Cochrane A
[Ad] Endereço:Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M5S1A8, Canada.
[Ti] Título:Identification of small molecule modulators of HIV-1 Tat and Rev protein accumulation.
[So] Source:Retrovirology;14(1):7, 2017 Jan 26.
[Is] ISSN:1742-4690
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: HIV-1 replication is critically dependent upon controlled processing of its RNA and the activities provided by its encoded regulatory factors Tat and Rev. A screen of small molecule modulators of RNA processing identified several which inhibited virus gene expression, affecting both relative abundance of specific HIV-1 RNAs and the levels of Tat and Rev proteins. RESULTS: The screen for small molecules modulators of HIV-1 gene expression at the post-transcriptional level identified three (a pyrimidin-7-amine, biphenylcarboxamide, and benzohydrazide, designated 791, 833, and 892, respectively) that not only reduce expression of HIV-1 Gag and Env and alter the accumulation of viral RNAs, but also dramatically decrease Tat and Rev levels. Analyses of viral RNA levels by qRTPCR and RTPCR indicated that the loss of either protein could not be attributed to changes in abundance of the mRNAs encoding these factors. However, addition of the proteasome inhibitor MG132 did result in significant restoration of Tat expression, indicating that the compounds are affecting Tat synthesis and/or degradation. Tests in the context of replicating HIV-1 in PBMCs confirmed that 791 significantly reduced virus replication. Parallel analyses of the effect of the compounds on host gene expression revealed only minor changes in either mRNA abundance or alternative splicing. Subsequent tests suggest that 791 may function by reducing levels of the Tat/Rev chaperone Nap1. CONCLUSIONS: The three compounds examined (791, 833, 892), despite their lack of structural similarity, all suppressed HIV-1 gene expression by preventing accumulation of two key HIV-1 regulatory factors, Tat and Rev. These findings demonstrate that selective disruption of HIV-1 gene expression can be achieved.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/isolamento & purificação
Fármacos Anti-HIV/farmacologia
Regulação Viral da Expressão Gênica/efeitos dos fármacos
HIV-1/genética
Processamento Pós-Transcricional do RNA/efeitos dos fármacos
Produtos do Gene rev do Vírus da Imunodeficiência Humana/antagonistas & inibidores
Produtos do Gene tat do Vírus da Imunodeficiência Humana/antagonistas & inibidores
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/química
Células Cultivadas
HIV-1/fisiologia
Seres Humanos
Modelos Moleculares
Estrutura Molecular
RNA Viral/análise
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (RNA, Viral); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170510
[Lr] Data última revisão:
170510
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170127
[St] Status:MEDLINE
[do] DOI:10.1186/s12977-017-0330-0


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[PMID]:27852860
[Au] Autor:Behrens RT; Aligeti M; Pocock GM; Higgins CA; Sherer NM
[Ad] Endereço:McArdle Laboratory for Cancer Research, Institute for Molecular Virology, and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
[Ti] Título:Nuclear Export Signal Masking Regulates HIV-1 Rev Trafficking and Viral RNA Nuclear Export.
[So] Source:J Virol;91(3), 2017 Feb 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1's Rev protein forms a homo-oligomeric adaptor complex linking viral RNAs to the cellular CRM1/Ran-GTP nuclear export machinery through the activity of Rev's prototypical leucine-rich nuclear export signal (NES). In this study, we used a functional fluorescently tagged Rev fusion protein as a platform to study the effects of modulating Rev NES identity, number, position, or strength on Rev subcellular trafficking, viral RNA nuclear export, and infectious virion production. We found that Rev activity was remarkably tolerant of diverse NES sequences, including supraphysiological NES (SNES) peptides that otherwise arrest CRM1 transport complexes at nuclear pores. Rev's ability to tolerate a SNES was both position and multimerization dependent, an observation consistent with a model wherein Rev self-association acts to transiently mask the NES peptide(s), thereby biasing Rev's trafficking into the nucleus. Combined imaging and functional assays also indicated that NES masking underpins Rev's well-known tendency to accumulate at the nucleolus, as well as Rev's capacity to activate optimal levels of late viral gene expression. We propose that Rev multimerization and NES masking regulates Rev's trafficking to and retention within the nucleus even prior to RNA binding. IMPORTANCE: HIV-1 infects more than 34 million people worldwide causing >1 million deaths per year. Infectious virion production is activated by the essential viral Rev protein that mediates nuclear export of intron-bearing late-stage viral mRNAs. Rev's shuttling into and out of the nucleus is regulated by the antagonistic activities of both a peptide-encoded N-terminal nuclear localization signal and C-terminal nuclear export signal (NES). How Rev and related viral proteins balance strong import and export activities in order to achieve optimal levels of viral gene expression is incompletely understood. We provide evidence that multimerization provides a mechanism by which Rev transiently masks its NES peptide, thereby biasing its trafficking to and retention within the nucleus. Targeted pharmacological disruption of Rev-Rev interactions should perturb multiple Rev activities, both Rev-RNA binding and Rev's trafficking to the nucleus in the first place.
[Mh] Termos MeSH primário: Transporte Ativo do Núcleo Celular
Infecções por HIV/virologia
HIV-1/fisiologia
Sinais de Localização Nuclear
Transporte de RNA
RNA Viral/metabolismo
Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Linhagem Celular
Células Cultivadas
Seres Humanos
Modelos Biológicos
Sinais de Localização Nuclear/química
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Replicação Viral
Produtos do Gene rev do Vírus da Imunodeficiência Humana/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nuclear Localization Signals); 0 (RNA, Viral); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161118
[St] Status:MEDLINE


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[PMID]:27353011
[Au] Autor:Upadhyay SK
[Ad] Endereço:CSIR-Institute of Genomics & Integrative Biology, New Delhi, 110020, India.
[Ti] Título:Binding and thermodynamics of REV peptide-ctDNA interaction.
[So] Source:Biopolymers;108(2), 2017 Mar.
[Is] ISSN:1097-0282
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The thermodynamics of DNA-ligand binding is important as it provides useful information to understand the details of binding processes. HIV-1 REV response element (RRE) located in the env coding region of the viral genome is reported to be well conserved across different HIV-1 isolates. In this study, the binding characteristics of Calf thymus DNA (ctDNA) and REV peptide from HIV-1 were investigated using spectroscopic (UV-visible, fluorescence, and circular dichroism (CD)) and isothermal titration calorimetric (ITC) techniques. Thermal stability and ligand binding properties of the ctDNA revealed that native ctDNA had a T of 75.5 °C, whereas the ctDNA-REV peptide complex exhibited an incremental shift in the T by 8 °C, indicating thermal stability of the complex. CD data indicated increased ellipticity due to large conformational changes in ctDNA molecule upon binding with REV peptide and two binding stoichiometric modes are apparent. The ctDNA experienced condensation due to large conformational changes in the presence of REV peptide and positive Bâ†’Ψ transition was observed at higher molar charge ratios. Fluorescence studies performed at several ligand concentrations revealed a gradual decrease in the fluorescence intensity of EtBr-bound ctDNA in response to increasing ligand concentrations. The fluorescence data further confirmed two stoichiometric modes of binding for ctDNA-REV peptide complex as previously observed with CD studies. The binding enthalpies were determined using ITC in the temperature range of 293 K-308 K. The ITC binding isotherm was exothermic at all temperatures examined, with low ΔH values indicating that the ctDNA-REV peptide interaction is driven largely by entropy. The heat capacity change (ΔC ) was insignificant, an unusual finding in the area of DNA-peptide interaction studies. The variation in the values obtained for ΔH, ΔS, and ΔG with temperature further suggests that ctDNA-REV peptide interaction is entropically driven. ITC based analysis of salt dependence of binding constant gave a charge value (Z) = +4.01, as determined for the δlnK/δln[Na ] parameter, suggesting the participation of only 3-4 Arg out of 11 Arg charge from REV peptide. The stoichiometry observed for the complex was three molar charge of REV peptide binding per molar charge of ctDNA. ITC based analysis further confirmed that the binding between ctDNA and REV peptide is governed by electrostatic interaction. Molecular interactions including H-bonding, van der Waals forces, and solvent molecules rearrangement, underlie the binding of REV peptide to ctDNA.
[Mh] Termos MeSH primário: DNA/química
Peptídeos/química
Termodinâmica
Produtos do Gene rev do Vírus da Imunodeficiência Humana/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação/genética
Calorimetria
Bovinos
Dicroísmo Circular
DNA/metabolismo
Entropia
HIV-1/genética
HIV-1/metabolismo
Temperatura Alta
Ligantes
Peptídeos/metabolismo
Ligação Proteica
Espectrofotometria
Eletricidade Estática
Produtos do Gene rev do Vírus da Imunodeficiência Humana/genética
Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Peptides); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1); 9007-49-2 (DNA); 91080-16-9 (calf thymus DNA)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170424
[Lr] Data última revisão:
170424
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160630
[St] Status:MEDLINE
[do] DOI:10.1002/bip.22902


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[PMID]:27984726
[Au] Autor:Fernandes JD; Faust TB; Strauli NB; Smith C; Crosby DC; Nakamura RL; Hernandez RD; Frankel AD
[Ad] Endereço:Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA; Program in Pharmaceutical Sciences and Pharmacogenomics, University of California San Francisco, San Francisco, CA 94158, USA.
[Ti] Título:Functional Segregation of Overlapping Genes in HIV.
[So] Source:Cell;167(7):1762-1773.e12, 2016 Dec 15.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Overlapping genes pose an evolutionary dilemma as one DNA sequence evolves under the selection pressures of multiple proteins. Here, we perform systematic statistical and mutational analyses of the overlapping HIV-1 genes tat and rev and engineer exhaustive libraries of non-overlapped viruses to perform deep mutational scanning of each gene independently. We find a "segregated" organization in which overlapped sites encode functional residues of one gene or the other, but never both. Furthermore, this organization eliminates unfit genotypes, providing a fitness advantage to the population. Our comprehensive analysis reveals the extraordinary manner in which HIV minimizes the constraint of overlapping genes and repurposes that constraint to its own advantage. Thus, overlaps are not just consequences of evolutionary constraints, but rather can provide population fitness advantages.
[Mh] Termos MeSH primário: Evolução Biológica
HIV-1/genética
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Entropia
Aptidão Genética
Infecções por HIV/virologia
Seres Humanos
Mutação
Fases de Leitura Aberta
Produtos do Gene rev do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170509
[Lr] Data última revisão:
170509
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE


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[PMID]:27265851
[Au] Autor:DiMattia MA; Watts NR; Cheng N; Huang R; Heymann JB; Grimes JM; Wingfield PT; Stuart DI; Steven AC
[Ad] Endereço:Laboratory of Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Headington OX
[Ti] Título:The Structure of HIV-1 Rev Filaments Suggests a Bilateral Model for Rev-RRE Assembly.
[So] Source:Structure;24(7):1068-80, 2016 Jul 06.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 Rev protein mediates the nuclear export of viral RNA genomes. To do so, Rev oligomerizes cooperatively onto an RNA motif, the Rev response element (RRE), forming a complex that engages with the host nuclear export machinery. To better understand Rev oligomerization, we determined four crystal structures of Rev N-terminal domain dimers, which show that they can pivot about their dyad axis, giving crossing angles of 90° to 140°. In parallel, we performed cryoelectron microscopy of helical Rev filaments. Filaments vary from 11 to 15 nm in width, reflecting variations in dimer crossing angle. These structures contain additional density, indicating that C-terminal domains become partially ordered in the context of filaments. This conformational variability may be exploited in the assembly of RRE/Rev complexes. Our data also revealed a third interface between Revs, which offers an explanation for how the arrangement of Rev subunits adapts to the "A"-shaped architecture of the RRE in export-active complexes.
[Mh] Termos MeSH primário: HIV-1/ultraestrutura
Multimerização Proteica
Produtos do Gene rev do Vírus da Imunodeficiência Humana/química
[Mh] Termos MeSH secundário: HIV-1/química
Ligação Proteica
Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160607
[St] Status:MEDLINE


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[PMID]:27232514
[Au] Autor:Bhoj VG; Thibodeaux SR; Levine BL
[Ad] Endereço:Department of Pathology and Laboratory Medicine and Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
[Ti] Título:Novel gene and cellular therapy approaches for treating HIV.
[So] Source:Discov Med;21(116):283-92, 2016 Apr.
[Is] ISSN:1944-7930
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Advances in HIV drug therapy have drastically decreased mortality and significantly improved quality of life for HIV infected patients since the early days of the epidemic. However, HIV drug-resistance, drug toxicities, therapy adherence, and the need for life-long treatment remain major challenges that continue to contribute to HIV-related global health concerns. Recent advances in cancer immunotherapy have proven the potency of cellular gene therapies. An ever-growing toolbox of methods of gene manipulation, cell modification, and clinical cell manufacturing, will enable moving beyond continuous drug therapy for more effective and durable treatments, including the possibility of inducing permanent resistance to HIV. These approaches, which target both host and viral factors, capitalize on points of vulnerability in the virus life cycle. Cellular and gene therapy has the potential to be an effective one-time therapy with less toxicity. Here, we review several promising strategies currently in pre-clinical development and clinical trials.
[Mh] Termos MeSH primário: Terapia Baseada em Transplante de Células e Tecidos/métodos
Terapia Genética/métodos
Infecções por HIV/terapia
HIV-1/fisiologia
Linfócitos T/transplante
[Mh] Termos MeSH secundário: Antirretrovirais/efeitos adversos
Antirretrovirais/uso terapêutico
Sistemas CRISPR-Cas/genética
Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos
Proteínas de Ligação a DNA/genética
Farmacorresistência Viral
Endorribonucleases/genética
Proteínas de Escherichia coli/genética
Técnicas de Transferência de Genes
Terapia Genética/efeitos adversos
Infecções por HIV/imunologia
HIV-1/efeitos dos fármacos
Seres Humanos
Qualidade de Vida
Receptores CCR5/genética
Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética
Transplante Autólogo/métodos
Produtos do Gene rev do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Retroviral Agents); 0 (CCR5 protein, human); 0 (DNA-Binding Proteins); 0 (Escherichia coli Proteins); 0 (MazF protein, E coli); 0 (Receptors, CCR5); 0 (rev Gene Products, Human Immunodeficiency Virus); EC 3.1.- (Endoribonucleases); EC 3.1.- (Transcription Activator-Like Effector Nucleases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160528
[St] Status:MEDLINE


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[PMID]:26929078
[Au] Autor:Fernandes JD; Booth DS; Frankel AD
[Ad] Endereço:Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
[Ti] Título:A structurally plastic ribonucleoprotein complex mediates post-transcriptional gene regulation in HIV-1.
[So] Source:Wiley Interdiscip Rev RNA;7(4):470-86, 2016 Jul.
[Is] ISSN:1757-7012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV replication requires the nuclear export of essential, intron-containing viral RNAs. To facilitate export, HIV encodes the viral accessory protein Rev which binds unspliced and partially spliced viral RNAs and creates a ribonucleoprotein complex that recruits the cellular Chromosome maintenance factor 1 export machinery. Exporting RNAs in this manner bypasses the necessity for complete splicing as a prerequisite for mRNA export, and allows intron-containing RNAs to reach the cytoplasm intact for translation and virus packaging. Recent structural studies have revealed that this entire complex exhibits remarkable plasticity at many levels of organization, including RNA folding, protein-RNA recognition, multimer formation, and host factor recruitment. In this review, we explore each aspect of plasticity from structural, functional, and possible therapeutic viewpoints. WIREs RNA 2016, 7:470-486. doi: 10.1002/wrna.1342 For further resources related to this article, please visit the WIREs website.
[Mh] Termos MeSH primário: Núcleo Celular/metabolismo
HIV-1/fisiologia
RNA Viral/metabolismo
Ribonucleoproteínas/metabolismo
Replicação Viral
Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Regulação Viral da Expressão Gênica
HIV-1/genética
Seres Humanos
Processamento Pós-Transcricional do RNA
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (RNA, Viral); 0 (Ribonucleoproteins); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160302
[St] Status:MEDLINE
[do] DOI:10.1002/wrna.1342


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[PMID]:26896646
[Au] Autor:Prado S; Beltrán M; Coiras M; Bedoya LM; Alcamí J; Gallego J
[Ad] Endereço:Facultad de Medicina, Universidad Católica de Valencia, C/Quevedo 2, 46001 Valencia, Spain.
[Ti] Título:Bioavailable inhibitors of HIV-1 RNA biogenesis identified through a Rev-based screen.
[So] Source:Biochem Pharmacol;107:14-28, 2016 May 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:New antiretroviral agents with alternative mechanisms are needed to complement the combination therapies used to treat HIV-1 infections. Here we report the identification of bioavailable molecules that interfere with the gene expression processes of HIV-1. The compounds were detected by screening a small library of FDA-approved drugs with an assay based on measuring the displacement of Rev, and essential virus-encoded protein, from its high-affinity RNA binding site. The antiretroviral activity of two hits was based on interference with post-integration steps of the HIV-1 cycle. Both hits inhibited RRE-Rev complex formation in vitro, and blocked LTR-dependent gene expression and viral transcription in cellular assays. The best compound altered the splicing pattern of HIV-1 transcripts in a manner consistent with Rev inhibition. This mechanism of action is different from those used by current antiretroviral agents. The screening hits recognized the Rev binding site in the viral RNA, and the best compound did so with substantial selectivity, allowing the identification of a new RNA-binding scaffold. These results may be used for developing novel antiretroviral drugs.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Regulação Viral da Expressão Gênica/efeitos dos fármacos
HIV-1/efeitos dos fármacos
RNA Viral/metabolismo
Elementos de Resposta/efeitos dos fármacos
Transcrição Genética/efeitos dos fármacos
Produtos do Gene rev do Vírus da Imunodeficiência Humana/antagonistas & inibidores
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/efeitos adversos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Clomifeno/efeitos adversos
Clomifeno/farmacologia
Ciproeptadina/efeitos adversos
Ciproeptadina/farmacologia
Avaliação Pré-Clínica de Medicamentos
Genes Reporter/efeitos dos fármacos
HIV-1/crescimento & desenvolvimento
HIV-1/metabolismo
Ensaios de Triagem em Larga Escala
Seres Humanos
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Processamento de RNA/efeitos dos fármacos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Bibliotecas de Moléculas Pequenas
Produtos do Gene rev do Vírus da Imunodeficiência Humana/química
Produtos do Gene rev do Vírus da Imunodeficiência Humana/genética
Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Peptide Fragments); 0 (RNA, Viral); 0 (Recombinant Proteins); 0 (Small Molecule Libraries); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1); 1HRS458QU2 (Clomiphene); 2YHB6175DO (Cyproheptadine)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160406
[Lr] Data última revisão:
160406
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160221
[St] Status:MEDLINE


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[PMID]:26751016
[Au] Autor:Jacobson JM; Routy JP; Welles S; DeBenedette M; Tcherepanova I; Angel JB; Asmuth DM; Stein DK; Baril JG; McKellar M; Margolis DM; Trottier B; Wood K; Nicolette C
[Ad] Endereço:*Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA; †Division of Hematology and Chronic Viral Illness Service, McGill University, Montreal, Quebec, Canada; ‡Department of Epidemiology and Biostatistics, Drexel University College of Medicine, Philadelphia, PA; §Argostherapeutics, Durham, NC; ‖Division of Infectious Diseases, The Ottawa Hospital and the University of Ottawa, Ottawa, CA; ¶Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA; #Department of Medicine, Albert Einstein College of Medicine, New York, NY; **Clinique Medicale du Quartier Latin, Montreal, Quebec, Canada; ††Duke University Medical Center, Durham, NC; ‡‡UNC HIV Cure Center and Departments of Medicine, Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC; §§Clinique Medicale l'Actuel, Montreal, Quebec, Canada; and ‖‖Frontier Science, Amherst, NY.
[Ti] Título:Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
[So] Source:J Acquir Immune Defic Syndr;72(1):31-8, 2016 May 01.
[Is] ISSN:1944-7884
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The genomic heterogeneity of HIV-1 impedes the ability of consensus sequences in vaccines to elicit effective antiviral immune responses. AGS-004 amplifies translation-competent RNA molecules encoding for Gag, Rev, Vpr, and Nef from the patient's autologous virus and loads them into dendritic cells. METHODS: This phase IIB, multicenter, 2:1 randomized, double-blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy with viral loads (VLs) <50 copies per milliliter, current CD4 T-cell counts >450 cells per cubic millimeter, and nadir counts >200 cells per cubic millimeter, to receive intradermal injections of study product into the axillary lymph node region every 4 weeks. At week 16, a 12-week analytical treatment interruption (ATI) was undertaken. RESULTS: There was no difference in the end-of-ATI VL (average of values from weeks 11 and 12) between the 2 arms of the study [4.39 (4.17, 4.69) vs. 4.47 (3.76, 4.64) log10 HIV-1 RNA; P = 0.73]. Between arms, no change between pre-antiretroviral therapy VL and the end-of-ATI VL [-0.06 (0.24, -0.32) vs. -0.17 (0.17, -0.32) log10 HIV-1 RNA; P = 0.43] was observed. When interferon-γ, interleukin-2, tumor necrosis factor α, CD107a, and granzyme b expressions were measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional cytotoxic T-lymphocyte responses induced in the CD28+/CD45RA-CD8 effector/memory T-cell population to dendritic cells electroporated with autologous antigens. Adverse events consisted of transient, mild (grade 1) local injection site reactions. CONCLUSIONS: Despite the induction of HIV-specific effector/memory CD8 T-cell responses, no antiviral effect was seen after the administration of AGS-004 when compared with placebo.
[Mh] Termos MeSH primário: Células Dendríticas/imunologia
Infecções por HIV/terapia
HIV-1/imunologia
Imunoterapia/métodos
RNA Viral/uso terapêutico
Linfócitos T Citotóxicos/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Contagem de Linfócito CD4
Linfócitos T CD4-Positivos/imunologia
Método Duplo-Cego
Feminino
Granzimas/biossíntese
HIV-1/genética
Seres Humanos
Interferon gama/biossíntese
Interleucina-2/biossíntese
Proteína 1 de Membrana Associada ao Lisossomo/biossíntese
Masculino
Meia-Idade
Placebos/uso terapêutico
Fator de Necrose Tumoral alfa/biossíntese
Carga Viral
Adulto Jovem
Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
Produtos do Gene rev do Vírus da Imunodeficiência Humana/genética
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IL2 protein, human); 0 (Interleukin-2); 0 (Lysosomal-Associated Membrane Protein 1); 0 (Placebos); 0 (RNA, Viral); 0 (Tumor Necrosis Factor-alpha); 0 (gag Gene Products, Human Immunodeficiency Virus); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1); 82115-62-6 (Interferon-gamma); EC 3.4.21.- (Granzymes)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170501
[Lr] Data última revisão:
170501
[Sb] Subgrupo de revista:IM; X
[Da] Data de entrada para processamento:160112
[St] Status:MEDLINE
[do] DOI:10.1097/QAI.0000000000000926



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