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[PMID]:28493473
[Au] Autor:Tahrir FG; Shanmughapriya S; Ahooyi TM; Knezevic T; Gupta MK; Kontos CD; McClung JM; Madesh M; Gordon J; Feldman AM; Cheung JY; Khalili K
[Ad] Endereço:Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
[Ti] Título:Dysregulation of mitochondrial bioenergetics and quality control by HIV-1 Tat in cardiomyocytes.
[So] Source:J Cell Physiol;233(2):748-758, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiovascular disease remains a leading cause of morbidity and mortality in HIV-positive patients, even in those whose viral loads are well controlled with antiretroviral therapy. However, the underlying molecular events responsible for the development of cardiac disease in the setting of HIV remain unknown. The HIV-encoded Tat protein plays a critical role in the activation of HIV gene expression and profoundly impacts homeostasis in both HIV-infected cells and uninfected cells that have taken up released Tat via a bystander effect. Since cardiomyocyte function, including excitation-contraction coupling, greatly depends on energy provided by the mitochondria, in this study, we performed a series of experiments to assess the impact of Tat on mitochondrial function and bioenergetics pathways in a primary cell culture model derived from neonatal rat ventricular cardiomyocytes (NRVCs). Our results show that the presence of Tat in cardiomyocytes is accompanied by a decrease in oxidative phosphorylation, a decline in the levels of ATP, and an accumulation of reactive oxygen species (ROS). Tat impairs the uptake of mitochondrial Ca ([Ca ] ) and the electrophysiological activity of cardiomyocytes. Tat also affects the protein clearance pathway and autophagy in cardiomyocytes under stress due to hypoxia-reoxygenation conditions. A reduction in the level of ubiquitin along with dysregulated degradation of autophagy proteins including SQSTM1/p62 and a reduction of LC3 II were detected in cardiomyocytes harboring Tat. These results suggest that, by targeting mitochondria and protein quality control, Tat significantly impacts bioenergetics and autophagy resulting in dysregulation of cardiomyocyte health and homeostasis.
[Mh] Termos MeSH primário: Metabolismo Energético
HIV-1/metabolismo
Mitocôndrias Cardíacas/metabolismo
Miócitos Cardíacos/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Animais
Apoptose
Autofagia
Cálcio/metabolismo
Canais de Cálcio/metabolismo
Hipóxia Celular
Células Cultivadas
Interações Hospedeiro-Patógeno
Potenciais da Membrana
Proteínas Associadas aos Microtúbulos/metabolismo
Mitocôndrias Cardíacas/virologia
Degradação Mitocondrial
Miócitos Cardíacos/virologia
Fosforilação Oxidativa
Cultura Primária de Células
Ratos Sprague-Dawley
Espécies Reativas de Oxigênio/metabolismo
Proteína Sequestossoma-1/metabolismo
Transdução de Sinais
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels); 0 (LC3 protein, rat); 0 (Microtubule-Associated Proteins); 0 (Reactive Oxygen Species); 0 (Sequestosome-1 Protein); 0 (Sqstm1 protein, rat); 0 (mitochondrial calcium uniporter); 0 (tat Gene Products, Human Immunodeficiency Virus); 8L70Q75FXE (Adenosine Triphosphate); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.26002


  2 / 3220 MEDLINE  
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[PMID]:28468838
[Au] Autor:Raja R; Ronsard L; Lata S; Trivedi S; Banerjea AC
[Ad] Endereço:Laboratory of Virology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India akhil@nii.res.in akhil@nii.ac.in rameezraaj88@gmail.com rameez@nii.ac.in.
[Ti] Título:HIV-1 Tat potently stabilises Mdm2 and enhances viral replication.
[So] Source:Biochem J;474(14):2449-2464, 2017 07 11.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Murine double minute 2 (Mdm2) is known to enhance the transactivation potential of human immunodeficiency virus (HIV-1) Tat protein by causing its ubiquitination. However, the regulation of Mdm2 during HIV-1 infection and its implications for viral replication have not been well studied. Here, we show that the Mdm2 protein level increases during HIV-1 infection and this effect is mediated by HIV-1 Tat protein. Tat appears to stabilise Mdm2 at the post-translational level by inducing its phosphorylation at serine-166 position through AKT. Although p53 is one of the key players for Mdm2 induction, Tat-mediated stabilisation of Mdm2 appears to be independent of p53. Moreover, the non-phosphorylatable mutant of Mdm2 (S166A) fails to interact with Tat and shows decreased half-life in the presence of Tat compared with wild-type Mdm2. Furthermore, the non-phosphorylatable mutant of Mdm2 (S166A) is unable to support HIV-1 replication. Thus, HIV-1 Tat appears to stabilise Mdm2, which in turn enhances Tat-mediated viral replication. This study highlights the importance of post-translational modifications of host cellular factors in HIV-1 replication and pathogenesis.
[Mh] Termos MeSH primário: HIV-1/fisiologia
Proteínas Proto-Oncogênicas c-mdm2/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Núcleo Celular/metabolismo
Técnicas de Silenciamento de Genes
Células HEK293
Seres Humanos
Mutação
Fosforilação
Proteínas Proto-Oncogênicas c-mdm2/genética
RNA Interferente Pequeno/genética
Proteína Supressora de Tumor p53/metabolismo
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Small Interfering); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 0 (tat Gene Products, Human Immunodeficiency Virus); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171217
[Lr] Data última revisão:
171217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20160825


  3 / 3220 MEDLINE  
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[PMID]:29045398
[Au] Autor:Razooky BS; Cao Y; Hansen MMK; Perelson AS; Simpson ML; Weinberger LS
[Ad] Endereço:Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America.
[Ti] Título:Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean.
[So] Source:PLoS Biol;15(10):e2000841, 2017 Oct.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fundamental to biological decision-making is the ability to generate bimodal expression patterns where 2 alternate expression states simultaneously exist. Here, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV's fate decision between active replication and viral latency. We find that the HIV transactivator of transcription (Tat) protein manipulates the intrinsic toggling of HIV's promoter, the long terminal repeat (LTR), to generate bimodal ON-OFF expression and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit's noncooperative "nonlatching" feedback architecture is optimized to slow the promoter's toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that nonlatching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV's decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuits may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.
[Mh] Termos MeSH primário: Retroalimentação Fisiológica
Regulação Viral da Expressão Gênica/genética
HIV-1/genética
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Algoritmos
Citometria de Fluxo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HEK293
Infecções por HIV/virologia
Repetição Terminal Longa de HIV/genética
HIV-1/fisiologia
Seres Humanos
Células Jurkat
Microscopia Confocal
Modelos Genéticos
Regiões Promotoras Genéticas/genética
Análise de Célula Única/métodos
Processos Estocásticos
Transcrição Genética
Latência Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (tat Gene Products, Human Immunodeficiency Virus); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171019
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2000841


  4 / 3220 MEDLINE  
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[PMID]:28800289
[Au] Autor:Pai A; Weinberger LS
[Ad] Endereço:Gladstone Institute of Virology and Immunology, San Francisco, California 94158; email: leor.weinberger@gladstone.ucsf.edu.
[Ti] Título:Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets.
[So] Source:Annu Rev Virol;4(1):469-490, 2017 Sep 29.
[Is] ISSN:2327-0578
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Current antivirals effectively target diverse viruses at various stages of their life cycles. Nevertheless, curative therapy has remained elusive for important pathogens, such as human immunodeficiency virus type 1 (HIV-1) and herpesviruses, in large part due to viral latency and the evolution of resistance to existing therapies. Here, we review the discovery of viral master circuits: virus-encoded autoregulatory gene networks that autonomously control viral expression programs (i.e., between active, latent, and abortive fates). These circuits offer the opportunity for a new class of antivirals that could lead to intrinsic combination-antiviral therapies within a single molecule-evolutionary escape from such circuit-disrupting antivirals would require simultaneous evolution of both the viral cis regulatory element (e.g., the DNA-binding site) and the trans element (e.g., the transcription factor) in order for the virus to recapitulate a circuit that would not be disrupted. We review the architectures of these fate-regulating master circuits in HIV-1 and the human herpesvirus cytomegalovirus along with potential circuit-disruption strategies that may ultimately enable escape-resistant antiviral therapies.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Antivirais/farmacologia
Citomegalovirus/genética
Regulação Viral da Expressão Gênica
Redes Reguladoras de Genes
HIV-1/genética
[Mh] Termos MeSH secundário: Citomegalovirus/efeitos dos fármacos
Citomegalovirus/fisiologia
Retroalimentação Fisiológica
HIV-1/efeitos dos fármacos
HIV-1/fisiologia
Seres Humanos
Fatores de Transcrição/metabolismo
Transcrição Genética
Latência Viral
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Antiviral Agents); 0 (Transcription Factors); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-virology-110615-035606


  5 / 3220 MEDLINE  
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[PMID]:28716964
[Au] Autor:Raybuck JD; Hargus NJ; Thayer SA
[Ad] Endereço:Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.
[Ti] Título:A GluN2B-Selective NMDAR Antagonist Reverses Synapse Loss and Cognitive Impairment Produced by the HIV-1 Protein Tat.
[So] Source:J Neurosci;37(33):7837-7847, 2017 Aug 16.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both and and has been linked to impaired neurocognitive function in humans. studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat. Here, we tested the hypothesis that Tat-induced loss and ifenprodil-mediated rescue of synaptic spines would predict impairment and rescue of cognitive function. Using intracranial multiphoton imaging, we found that infusion of 100 ng of HIV-1 Tat into the lateral ventricle of yellow fluorescent protein-expressing transgenic mice produced a 17 ± 1% loss of dendritic spines in layer 1 of retrosplenial cortex. Repeated imaging of the same dendrites over 3 weeks enabled longitudinal experiments that demonstrated sustained spine loss after Tat infusion and transient rescue after ifenprodil administration (10 mg/kg, i.p.). Parallel trace fear conditioning experiments showed that spine loss predicted learning deficits and that the time course of ifenprodil-induced rescue of spine density correlated with restoration of cognitive function. These results show for the first time that, during exposure to an HIV-1 neurotoxin , alteration of GluN2B-containing NMDAR signaling suppresses spine density and impairs learning. Pharmacological inhibition of these NMDARs rescued spines and restored cognitive function. Drugs that rescue synapses may improve neurocognitive function in HAND. Synaptodendritic damage correlates with cognitive decline in HIV-associated neurocognitive disorder (HAND) patients. We developed an imaging approach for longitudinal tracking of spine density that enabled correlation of synaptic changes with behavioral outcomes in a model of HAND. We show for the first time that spine loss after exposure to an HIV-1 protein can be reversed pharmacologically and that loss and recovery of dendritic spines predict impairment and restoration of cognitive function, respectively. Therefore, synapse loss, the hallmark of cognitive decline in HAND, is reversible. Drugs that restore spine density may have broad application for improving cognitive function during the early phases of neurodegenerative diseases.
[Mh] Termos MeSH primário: Disfunção Cognitiva/prevenção & controle
Antagonistas de Aminoácidos Excitatórios/administração & dosagem
HIV-1
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
Sinapses/efeitos dos fármacos
Produtos do Gene tat do Vírus da Imunodeficiência Humana/toxicidade
[Mh] Termos MeSH secundário: Animais
Disfunção Cognitiva/induzido quimicamente
Disfunção Cognitiva/metabolismo
Infusões Intraventriculares
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos CBA
Camundongos Transgênicos
Piperidinas/administração & dosagem
Receptores de N-Metil-D-Aspartato/metabolismo
Sinapses/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Excitatory Amino Acid Antagonists); 0 (NR2B NMDA receptor); 0 (Piperidines); 0 (Receptors, N-Methyl-D-Aspartate); 0 (tat Gene Products, Human Immunodeficiency Virus); R8OE3P6O5S (ifenprodil)
[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:170719
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0226-17.2017


  6 / 3220 MEDLINE  
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[PMID]:28715973
[Au] Autor:Mbonye U; Karn J
[Ad] Endereço:Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; email: jonathan.karn@case.edu.
[Ti] Título:The Molecular Basis for Human Immunodeficiency Virus Latency.
[So] Source:Annu Rev Virol;4(1):261-285, 2017 Sep 29.
[Is] ISSN:2327-0578
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although potent combination antiretroviral therapy can effectively block viral replication in the host, human immunodeficiency virus (HIV) persists due to the existence of latent but replication-competent proviruses residing primarily in a very small population of resting memory CD4 T cells. Viral latency is established when the expression of the autoregulatory viral trans-activating factor Tat is reduced to subthreshold levels. The absence of Tat reduces HIV transcription and protein production to levels that make the host cell invisible to the immune system and refractory to antiretroviral treatment. Key host cell mechanisms that drive HIV into latency are sequestration of transcription initiation factors, establishment of epigenetic barriers inactivating the proviral promoter, and blockage of the assembly of the host elongation factor P-TEFb. This comprehensive understanding of the molecular control of HIV transcription is leading to the development of optimized combinatorial reactivation and immune surveillance strategies designed to purge the latent viral reservoir.
[Mh] Termos MeSH primário: Regulação Viral da Expressão Gênica
HIV-1/genética
HIV-1/fisiologia
Transcrição Genética
Latência Viral/genética
[Mh] Termos MeSH secundário: Linfócitos T CD4-Positivos/virologia
Interações Hospedeiro-Patógeno
Seres Humanos
Fator B de Elongação Transcricional Positiva/genética
Regiões Promotoras Genéticas
Provírus/genética
Provírus/fisiologia
Replicação Viral
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (tat Gene Products, Human Immunodeficiency Virus); EC 2.7.11.- (Positive Transcriptional Elongation Factor B)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-virology-101416-041646


  7 / 3220 MEDLINE  
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[PMID]:28711733
[Au] Autor:Farokhinejad F; Behbahani AB; Rafiei Dehbidi GR; Takhshid MA
[Ad] Endereço:Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran; Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: Farokhinej
[Ti] Título:Expression and purification of TAT-NDRG2 recombinant protein and evaluation of its anti-proliferative effect on LNCaP cell line.
[So] Source:Protein Expr Purif;138:25-33, 2017 Oct.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N-myc downstream regulated gene2 (NDRG2) belongs to tumor suppressor protein family of NDRG. Anti-proliferative and anti-metastasis of NDRG2 overexpression has been demonstrated in a number of tumors. The aim of this study was to fuse the gene of Trans Activator of Transcription (TAT) protein transduction domain with NDRG2 gene and express and purify TAT-NDRG2 fusion protein in order to investigate the effects of TAT-NDRG2 protein on proliferation and apoptosis of LNCaP prostate carcinoma cell line. pET28a-TAT-NDRG2 and pET28a-NDRG2 plasmids were constructed and transformed into E. coli-BL21(DE3). TAT-NDRG2 and NDRG2 proteins were expressed in the bacteria, purified using affinity chromatography and verified using western blotting. The effects of TAT-NDRG2 and NDRG2 protein treatment on LNCaP cells proliferation and apoptosis were evaluated using MTT assay and AnnexinV, 7-AAD flow cytometry assay, respectively. Western blot analysis confirmed the expression and purification of TAT-NDRG2 and NDRG2 proteins. Treatment of LNCaP cells with TAT-NDRG2 protein increased cell death and induced apoptosis significantly (P < 0.05) compared to control and NDRG2 protein-treated cells. These results suggest that TAT-NDRG2 protein can be considered as a therapeutic modality for the treatment of tumors.
[Mh] Termos MeSH primário: Antineoplásicos/metabolismo
Apoptose/efeitos dos fármacos
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Supressoras de Tumor/biossíntese
Produtos do Gene tat do Vírus da Imunodeficiência Humana/biossíntese
[Mh] Termos MeSH secundário: Antineoplásicos/isolamento & purificação
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Seres Humanos
Corpos de Inclusão/química
Masculino
Plasmídeos/química
Plasmídeos/metabolismo
Próstata/efeitos dos fármacos
Próstata/metabolismo
Próstata/patologia
Dobramento de Proteína
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/farmacologia
Solubilidade
Proteínas Supressoras de Tumor/genética
Proteínas Supressoras de Tumor/isolamento & purificação
Proteínas Supressoras de Tumor/farmacologia
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
Produtos do Gene tat do Vírus da Imunodeficiência Humana/isolamento & purificação
Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (NDRG2 protein, human); 0 (Recombinant Fusion Proteins); 0 (Tumor Suppressor Proteins); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


  8 / 3220 MEDLINE  
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[PMID]:28699853
[Au] Autor:Oteiza A; Mechti N
[Ad] Endereço:CNRS UMR5235, DIMNP, Université de Montpellier, Bat 24, CC107, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
[Ti] Título:FoxO4 negatively controls Tat-mediated HIV-1 transcription through the post-transcriptional suppression of Tat encoding mRNA.
[So] Source:J Gen Virol;98(7):1864-1878, 2017 Jul.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The connection between the repression of human immunodeficiency virus type 1(HIV-1) transcription and the resting CD4+ T cell state suggests that the host transcription factors involved in the active maintenance of lymphocyte quiescence are likely to repress the viral transactivator, Tat, thereby restricting HIV-1 transcription. In this study, we analysed the interplay between Tat and the forkhead box transcription factors, FoxO1 and FoxO4. We show that FoxO1 and FoxO4 antagonize Tat-mediated transactivation of HIV-1 promoter through the repression of Tat protein expression. No effect was observed on the expression of two HIV-1 accessory proteins, Vif and Vpr. Unexpectedly, we found that FoxO1 and FoxO4 expression causes a strong dose-dependent post-transcriptional suppression of Tat mRNA, indicating that FoxO should effectively inhibit HIV-1 replication by destabilizing Tat mRNA and suppressing Tat-mediated HIV-1 transcription. In accordance with this, we observed that the Tat mRNA half-life is reduced by FoxO4 expression. The physiological relevance of our findings was validated using the J-Lat 10.6 model of latently infected cells. We demonstrated that the overexpression of a constitutively active FoxO4-TM mutant antagonized HIV-1 transcription reactivation in response to T cell activators, such as TNF-α or PMA. Altogether, our findings demonstrate that FoxO factors can control HIV-1 transcription and provide new insights into their potential role during the establishment of HIV-1 latency.
[Mh] Termos MeSH primário: Regulação Viral da Expressão Gênica
Infecções por HIV/metabolismo
HIV-1/genética
Fatores de Transcrição/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Proteína Forkhead Box O1/genética
Proteína Forkhead Box O1/metabolismo
Infecções por HIV/genética
Infecções por HIV/virologia
HIV-1/metabolismo
Seres Humanos
Regiões Promotoras Genéticas
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Fatores de Transcrição/genética
Ativação Transcricional
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FOXO1 protein, human); 0 (FOXO4 protein, human); 0 (Forkhead Box Protein O1); 0 (RNA, Messenger); 0 (Transcription Factors); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1099/jgv.0.000837


  9 / 3220 MEDLINE  
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[PMID]:28698313
[Au] Autor:Gajanayaka N; O'Hara S; Konarski Y; Fernandes J; Muthumani K; Kozlowski M; Angel JB; Kumar A
[Ad] Endereço:Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
[Ti] Título:HIV and HIV-Tat inhibit LPS-induced IL-27 production in human macrophages by distinct intracellular signaling pathways.
[So] Source:J Leukoc Biol;102(3):925-939, 2017 Sep.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Monocyte-derived MÏ•s (MDMs) from HIV-infected patients and MDM infected in vitro with HIV exhibit a reduced ability to secrete various cytokines, including IL-12. Recently, IL-27, an IL-12 family cytokine, was shown to inhibit HIV replication in MÏ•. Whether HIV infection or HIV accessory protein(s) impact IL-27 production in MÏ•s remains unknown. Herein, we show that in vitro HIV infection, as well as intracellular HIV-Tat (Tat) and Tat peptides, inhibit LPS-induced IL-27 production in human MDMs, suggesting impairment of the TLR4 signaling pathway. To understand the signaling pathways governing HIV or Tat-mediated inhibition of LPS-induced IL-27 production, we first demonstrated that p38 MAPK, PI3K, Src-homology region 2 domain-containing tyrosine phosphatase 1 (SHP-1), and Src kinases regulate LPS-induced IL-27 production in MDMs. Tat caused down-regulation of TNFR-associated factor (TRAF)-6 and inhibitor of apoptosis 1 (cIAP-1) and subsequently decreased phosphorylation of downstream PI3K and p38 MAPKs, which were implicated in LPS-induced IL-27 production. Whereas SHP-1 and Src kinases regulated LPS-induced IL-27 production, Tat did not inhibit these kinases, suggesting that they were not involved in Tat-mediated inhibition of LPS-induced IL-27 production. In contrast to Tat, in vitro HIV infection of MDM inhibited LPS-induced IL-27 production via inhibition of p38 MAPK activation. Overall, HIV and Tat inhibit LPS-induced IL-27 production in human macrophages via distinct mechanisms: Tat through the inhibition of cIAP-1-TRAF-6 and subsequent inhibition of PI3K and p38 MAPKs, whereas HIV through the inhibition of p38 MAPK activation.
[Mh] Termos MeSH primário: Infecções por HIV/imunologia
HIV-1/imunologia
Interleucinas/imunologia
Lipopolissacarídeos/farmacologia
Macrófagos/imunologia
Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia
[Mh] Termos MeSH secundário: Seres Humanos
Proteínas Inibidoras de Apoptose/imunologia
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Sistema de Sinalização das MAP Quinases/imunologia
Fosfatidilinositol 3-Quinases/imunologia
Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia
Fator 6 Associado a Receptor de TNF/imunologia
Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL27 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (Interleukins); 0 (Lipopolysaccharides); 0 (TNF Receptor-Associated Factor 6); 0 (Tifab protein, human); 0 (tat Gene Products, Human Immunodeficiency Virus); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.4A0716-332RR


  10 / 3220 MEDLINE  
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[PMID]:28640909
[Au] Autor:Carvallo L; Lopez L; Fajardo JE; Jaureguiberry-Bravo M; Fiser A; Berman JW
[Ad] Endereço:Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
[Ti] Título:HIV-Tat regulates macrophage gene expression in the context of neuroAIDS.
[So] Source:PLoS One;12(6):e0179882, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite the success of cART, greater than 50% of HIV infected people develop cognitive and motor deficits termed HIV-associated neurocognitive disorders (HAND). Macrophages are the major cell type infected in the CNS. Unlike for T cells, the virus does not kill macrophages and these long-lived cells may become HIV reservoirs in the brain. They produce cytokines/chemokines and viral proteins that promote inflammation and neuronal damage, playing a key role in HIV neuropathogenesis. HIV Tat is the transactivator of transcription that is essential for replication and transcriptional regulation of the virus and is the first protein to be produced after HIV infection. Even with successful cART, Tat is produced by infected cells. In this study we examined the role of the HIV Tat protein in the regulation of gene expression in human macrophages. Using THP-1 cells, a human monocyte/macrophage cell line, and their infection with lentivirus, we generated stable cell lines that express Tat-Flag. We performed ChIP-seq analysis of these cells and found 66 association sites of Tat in promoter or coding regions. Among these are C5, CRLF2/TSLPR, BDNF, and APBA1/Mint1, genes associated with inflammation/damage. We confirmed the association of Tat with these sequences by ChIP assay and expression of these genes in our THP-1 cell lines by qRT-PCR. We found that HIV Tat increased expression of C5, APBA1, and BDNF, and decreased CRLF2. The K50A Tat-mutation dysregulated expression of these genes without affecting the binding of the Tat complex to their gene sequences. Our data suggest that HIV Tat, produced by macrophage HIV reservoirs in the brain despite successful cART, contributes to neuropathogenesis in HIV-infected people.
[Mh] Termos MeSH primário: Complexo AIDS Demência/imunologia
Regulação da Expressão Gênica
Macrófagos/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Complexo AIDS Demência/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Substituição de Aminoácidos
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Diferenciação Celular
Linhagem Celular
Complemento C5/metabolismo
Seres Humanos
Macrófagos/citologia
Macrófagos/virologia
Proteínas do Tecido Nervoso/metabolismo
Receptores de Citocinas/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APBA1 protein, human); 0 (Adaptor Proteins, Signal Transducing); 0 (Brain-Derived Neurotrophic Factor); 0 (CRLF2 protein, human); 0 (Complement C5); 0 (Nerve Tissue Proteins); 0 (Receptors, Cytokine); 0 (tat Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179882



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