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[PMID]:28880280
[Au] Autor:Baxter AE; Niessl J; Fromentin R; Richard J; Porichis F; Massanella M; Brassard N; Alsahafi N; Routy JP; Finzi A; Chomont N; Kaufmann DE
[Ad] Endereço:Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM) and Université de Montréal, Montreal, Quebec, Canada.
[Ti] Título:Multiparametric characterization of rare HIV-infected cells using an RNA-flow FISH technique.
[So] Source:Nat Protoc;12(10):2029-2049, 2017 Oct.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Efforts to cure HIV are hampered by limited characterization of the cells supporting HIV replication in vivo and inadequate methods for quantifying the latent viral reservoir in individuals receiving antiretroviral therapy (ART). We describe a protocol for flow cytometric identification of viral reservoirs, based on concurrent detection of cellular HIV Gagpol mRNA by in situ RNA hybridization combined with antibody staining for the HIV Gag protein. By simultaneously detecting both HIV RNA and protein, the CD4 T cells harboring translation-competent virus can be identified. The HIV method is 1,000-fold more sensitive than Gag protein staining alone, with a detection limit of 0.5-1 Gagpol mRNA /Gag protein cells per million CD4 T cells. Uniquely, the HIV assay also allows parallel phenotyping of viral reservoirs, including reactivated latent reservoirs in clinical samples. The assay takes 2 d, and requires antibody labeling for surface and intracellular markers, followed by mRNA labeling and multiple signal amplification steps.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/virologia
Citometria de Fluxo/métodos
Infecções por HIV/diagnóstico
Infecções por HIV/virologia
Hibridização in Situ Fluorescente/métodos
RNA Viral/sangue
[Mh] Termos MeSH secundário: Proteínas de Fusão gag-pol/genética
Seres Humanos
Limite de Detecção
RNA Mensageiro/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fusion Proteins, gag-pol); 0 (RNA, Messenger); 0 (RNA, Viral)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2017.079


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[PMID]:28553933
[Au] Autor:Sanyal A; Mailliard RB; Rinaldo CR; Ratner D; Ding M; Chen Y; Zerbato JM; Giacobbi NS; Venkatachari NJ; Patterson BK; Chargin A; Sluis-Cremer N; Gupta P
[Ad] Endereço:Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
[Ti] Título:Novel assay reveals a large, inducible, replication-competent HIV-1 reservoir in resting CD4 T cells.
[So] Source:Nat Med;23(7):885-889, 2017 Jul.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although antiretroviral therapy can suppress HIV-1 infection to undetectable levels of plasma viremia, integrated latent HIV-1 genomes that encode replication-competent virus persist in resting CD4 T cells. This latent HIV-1 reservoir represents a major barrier to a cure. Currently, there are substantial efforts to identify therapeutic approaches that will eliminate or reduce the size of this latent HIV-1 reservoir. In this regard, a sensitive assay that can accurately and rapidly quantify inducible, replication-competent latent HIV-1 from resting CD4 T cells is essential for HIV-1 eradication studies. Here we describe a reporter cell-based assay to quantify inducible, replication-competent latent HIV-1. This assay has several advantages over existing technology in that it (i) is sensitive; (ii) requires only a small blood volume; (iii) is faster, less labor intensive, and less expensive; and (iv) can be readily adapted into a high-throughput format. Using this assay, we show that the size of the inducible latent HIV-1 reservoir in aviremic participants on therapy is approximately 70-fold larger than previous estimates.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/virologia
DNA Viral/análise
Infecções por HIV/virologia
HIV-1/genética
RNA Viral/análise
Carga Viral/métodos
[Mh] Termos MeSH secundário: Adulto
Idoso
Fármacos Anti-HIV/uso terapêutico
Feminino
Proteínas de Fusão gag-pol/genética
Infecções por HIV/tratamento farmacológico
Seres Humanos
Masculino
Meia-Idade
Latência Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (DNA, Viral); 0 (Fusion Proteins, gag-pol); 0 (RNA, Viral)
[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:170530
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4347


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[PMID]:28250114
[Au] Autor:Yu FH; Huang KJ; Wang CT
[Ad] Endereço:Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
[Ti] Título:C-Terminal HIV-1 Transframe p6* Tetrapeptide Blocks Enhanced Gag Cleavage Incurred by Leucine Zipper Replacement of a Deleted p6* Domain.
[So] Source:J Virol;91(10), 2017 May 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 protease (PR) functions as a homodimer mediating virus maturation following virus budding. Gag-Pol dimerization is believed to trigger embedded PR activation by promoting PR dimer formation. Early PR activation can lead to markedly reduced virus yields due to premature Gag cleavage. The p6* peptide, located between Gag and PR, is believed to ensure virus production by preventing early PR maturation. Studies aimed at finding supporting evidence for this proposal are limited due to a reading frame overlap between p6* and the p6gag budding domain. To determine if p6* affects virus production via the modulation of PR activation, we engineered multiple constructs derived from Dp6*PR (an assembly- and processing-competent construct with Pol fused at the inactivated PR C terminus). The data indicated that a p6* deletion adjacent to active PR significantly impaired virus processing. We also observed that the insertion of a leucine zipper (LZ) dimerization motif in the deleted region eliminated virus production in a PR activity-dependent manner, suggesting that the LZ insertion triggered premature PR activation by facilitating PR dimer formation. As few as four C-terminal p6* residues remaining at the p6*/PR junction were sufficient to restore virus yields, with a Gag processing profile similar to that of the wild type. Our study provides supporting evidence in a virus assembly context that the C-terminal p6* tetrapeptide plays a role in preventing premature PR maturation. Supporting evidence for the assumption that p6* retards PR maturation in the context of virus assembly is lacking. We found that replacing p6* with a leucine zipper peptide abolished virus assembly due to the significant enhancement of Gag cleavage. However, as few as four C-terminal p6* residues remaining in the deleted region were sufficient for significant PR release, as well as for counteracting leucine zipper-incurred premature Gag cleavage. Our data provide evidence that (i) p6* ensures virus assembly by preventing early PR activation and (ii) four C-terminal p6* residues are critical for modulating PR activation. Current PR inhibitor development efforts are aimed largely at mature PR, but there is a tendency for HIV-1 variants that are resistant to multiple protease inhibitors to emerge. Our data support the idea of modulating PR activation by targeting PR precursors as an alternative approach to controlling HIV-1/AIDS.
[Mh] Termos MeSH primário: Protease de HIV/metabolismo
Zíper de Leucina
Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas de Fusão gag-pol/genética
Proteínas de Fusão gag-pol/metabolismo
Protease de HIV/genética
HIV-1/enzimologia
HIV-1/fisiologia
Zíper de Leucina/genética
Deleção de Sequência
Montagem de Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fusion Proteins, gag-pol); 0 (gag Gene Products, Human Immunodeficiency Virus); EC 3.4.23.- (HIV Protease); EC 3.4.23.- (p16 protease, Human immunodeficiency virus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE


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[PMID]:27558426
[Au] Autor:La Porte A; Cano J; Wu X; Mitra D; Kalpana GV
[Ad] Endereço:Departments of Genetics and Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York.
[Ti] Título:An Essential Role of INI1/hSNF5 Chromatin Remodeling Protein in HIV-1 Posttranscriptional Events and Gag/Gag-Pol Stability.
[So] Source:J Virol;90(21):9889-9904, 2016 Nov 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INI1/hSNF5/SMARCB1/BAF47 is an HIV-specific integrase (IN)-binding protein that influences HIV-1 transcription and particle production. INI1 binds to SAP18 (Sin3a-associated protein, 18 kDa), and both INI1 and SAP18 are incorporated into HIV-1 virions. To determine the significance of INI1 and the INI1-SAP18 interaction during HIV-1 replication, we isolated a panel of SAP18-interaction-defective (SID)-INI1 mutants using a yeast reverse two-hybrid screen. The SID-INI1 mutants, which retained the ability to bind to IN, cMYC, and INI1 but were impaired for binding to SAP18, were tested for their effects on HIV-1 particle production. SID-INI1 dramatically reduced the intracellular Gag/Gag-Pol protein levels and, in addition, decreased viral particle production. The SID-INI1-mediated effects were less dramatic in trans complementation assays using IN deletion mutant viruses with Vpr-reverse transcriptase (RT)-IN. SID-INI1 did not inhibit long-terminal-repeat (LTR)-mediated transcription, but it marginally decreased the steady-state gag RNA levels, suggesting a posttranscriptional effect. Pulse-chase analysis indicated that in SID-INI1-expressing cells, the pr55Gag levels decreased rapidly. RNA interference analysis indicated that small hairpin RNA (shRNA)-mediated knockdown of INI1 reduced the intracellular Gag/Gag-Pol levels and further inhibited HIV-1 particle production. These results suggest that SID-INI1 mutants inhibit multiple stages of posttranscriptional events of HIV-1 replication, including intracellular Gag/Gag-Pol RNA and protein levels, which in turn inhibits assembly and particle production. Interfering INI1 leads to a decrease in particle production and Gag/Gag-Pol protein levels. Understanding the role of INI1 and SAP18 in HIV-1 replication is likely to provide novel insight into the stability of Gag/Gag-Pol, which may lead to the development of novel therapeutic strategies to inhibit HIV-1 late events. IMPORTANCE: Significant gaps exist in our current understanding of the mechanisms and host factors that influence HIV-1 posttranscriptional events, including gag RNA levels, Gag/Gag-Pol protein levels, assembly, and particle production. Our previous studies suggested that the IN-binding host factor INI1 plays a role in HIV-1 assembly. An ectopically expressed minimal IN-binding domain of INI1, S6, potently and selectively inhibited HIV-1 Gag/Gag-Pol trafficking and particle production. However, whether or not endogenous INI1 and its interacting partners, such as SAP18, are required for late events was unknown. Here, we report that endogenous INI1 and its interaction with SAP18 are necessary to maintain intracellular levels of Gag/Gag-Pol and for particle production. Interfering INI1 or the INI1-SAP18 interaction leads to the impairment of these processes, suggesting a novel strategy for inhibiting posttranscriptional events of HIV-1 replication.
[Mh] Termos MeSH primário: Montagem e Desmontagem da Cromatina/genética
Cromatina/genética
Proteínas de Fusão gag-pol/genética
HIV-1/genética
Processamento Pós-Transcricional do RNA/genética
Proteína SMARCB1/genética
Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Proteínas de Transporte/metabolismo
Linhagem Celular
Replicação do DNA/genética
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Proteínas de Fusão gag-pol/metabolismo
Células HEK293
Integrase de HIV/genética
Integrase de HIV/metabolismo
HIV-1/metabolismo
Seres Humanos
Proteína SMARCB1/metabolismo
Replicação Viral/genética
Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Chromatin); 0 (DNA-Binding Proteins); 0 (Fusion Proteins, gag-pol); 0 (SAP18 protein, human); 0 (SMARCB1 Protein); 0 (SMARCB1 protein, human); 0 (gag Gene Products, Human Immunodeficiency Virus); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170505
[Lr] Data última revisão:
170505
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160826
[St] Status:MEDLINE


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[PMID]:27341835
[Au] Autor:Mosabbir AA; Truong K
[Ad] Endereço:Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
[Ti] Título:Genomic integration occurs in the packaging cell via unexported lentiviral precursors.
[So] Source:Biotechnol Lett;38(10):1715-21, 2016 Oct.
[Is] ISSN:1573-6776
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To use HIV-1 based lentivirus components to produce gene integration and the formation of a stable cell line in the packaging cell line without viral infection. RESULTS: A co-transfection of a Human Embryonic Kidney (HEK) 293 packaging cell line with Gag-pol (GP) and a transfer vector, without the envelope vector, produces a stable cell line after 2 weeks of selection. Furthermore, a matrix protein deficient GP in the packaging vector enhances this integration. This supports that, in theory, unexported lentiviral cores produced within the packaging cell can infect itself without requiring the release of any lentiviral particles. CONCLUSION: If the packaging cell is also the target cell, then gene integration leading to a stable cell line can be accomplished without viral particle infection.
[Mh] Termos MeSH primário: Proteínas de Fusão gag-pol/genética
HIV-1/genética
Transfecção/métodos
[Mh] Termos MeSH secundário: Células 3T3
Animais
Empacotamento do DNA
Vetores Genéticos
Células HEK293
Seres Humanos
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fusion Proteins, gag-pol)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170203
[Lr] Data última revisão:
170203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160626
[St] Status:MEDLINE
[do] DOI:10.1007/s10529-016-2164-6


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[PMID]:27194769
[Au] Autor:Garcia-Miranda P; Becker JT; Benner BE; Blume A; Sherer NM; Butcher SE
[Ad] Endereço:Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA McArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
[Ti] Título:Stability of HIV Frameshift Site RNA Correlates with Frameshift Efficiency and Decreased Virus Infectivity.
[So] Source:J Virol;90(15):6906-17, 2016 Aug 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Human immunodeficiency virus (HIV) replication is strongly dependent upon a programmed ribosomal frameshift. Here we investigate the relationships between the thermodynamic stability of the HIV type 1 (HIV-1) RNA frameshift site stem-loop, frameshift efficiency, and infectivity, using pseudotyped HIV-1 and HEK293T cells. The data reveal a strong correlation between frameshift efficiency and local, but not overall, RNA thermodynamic stability. Mutations that modestly increase the local stability of the frameshift site RNA stem-loop structure increase frameshift efficiency 2-fold to 3-fold in cells. Thus, frameshift efficiency is determined by the strength of the thermodynamic barrier encountered by the ribosome. These data agree with previous in vitro measurements, suggesting that there are no virus- or host-specific factors that modulate frameshifting. The data also indicate that there are no sequence-specific requirements for the frameshift site stem-loop. A linear correlation between Gag-polymerase (Gag-Pol) levels in cells and levels in virions supports the idea of a stochastic virion assembly mechanism. We further demonstrate that the surrounding genomic RNA secondary structure influences frameshift efficiency and that a mutation that commonly arises in response to protease inhibitor therapy creates a functional but inefficient secondary slippery site. Finally, HIV-1 mutants with enhanced frameshift efficiencies are significantly less infectious, suggesting that compounds that increase frameshift efficiency by as little as 2-fold may be effective at suppressing HIV-1 replication. IMPORTANCE: HIV, like many retroviruses, utilizes a -1 programmed ribosomal frameshift to generate viral enzymes in the form of a Gag-Pol polyprotein precursor. Thus, frameshifting is essential for viral replication. Here, we utilized a panel of mutant HIV strains to demonstrate that in cells, frameshifting efficiency is correlated with the stability of the local thermodynamic barrier to ribosomal translocation. Increasing the stability of the frameshift site RNA increases the frameshift efficiency 2-fold to 3-fold. Mutant viruses with increased frameshift efficiencies have significantly reduced infectivity. These data suggest that this effect might be exploited in the development of novel antiviral strategies.
[Mh] Termos MeSH primário: Mutação da Fase de Leitura/genética
Mudança da Fase de Leitura do Gene Ribossômico/genética
Proteínas de Fusão gag-pol/metabolismo
Infecções por HIV/virologia
HIV-1/genética
RNA Viral/genética
Vírion/fisiologia
[Mh] Termos MeSH secundário: Pareamento de Bases
Sequência de Bases
Regulação Viral da Expressão Gênica
Células HEK293
Infecções por HIV/genética
HIV-1/química
HIV-1/metabolismo
Seres Humanos
Conformação de Ácido Nucleico
Estabilidade de RNA
RNA Viral/química
RNA Viral/metabolismo
Montagem de Vírus
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fusion Proteins, gag-pol); 0 (RNA, Viral)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160520
[St] Status:MEDLINE
[do] DOI:10.1128/JVI.00149-16


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[PMID]:26718849
[Au] Autor:Thippeshappa R; Tian B; Cleveland B; Guo W; Polacino P; Hu SL
[Ad] Endereço:Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
[Ti] Título:Oral Immunization with Recombinant Vaccinia Virus Prime and Intramuscular Protein Boost Provides Protection against Intrarectal Simian-Human Immunodeficiency Virus Challenge in Macaques.
[So] Source:Clin Vaccine Immunol;23(3):204-12, 2015 Dec 30.
[Is] ISSN:1556-679X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human immunodeficiency virus type 1 (HIV-1) acquisition occurs predominantly through mucosal transmission. We hypothesized that greater mucosal immune responses and protective efficacy against mucosal HIV-1 infection may be achieved by prime-boost immunization at mucosal sites. We used a macaque model to determine the safety, immunogenicity, and protective efficacy of orally delivered, replication-competent but attenuated recombinant vaccinia viruses expressing full-length HIV-1 SF162 envelope (Env) or simian immunodeficiency virus (SIV) Gag-Pol proteins. We examined the dose and route that are suitable for oral immunization with recombinant vaccinia viruses. We showed that sublingual inoculation of two vaccinia virus-naive pigtailed macaques with 5 × 10(8) PFU of recombinant vaccinia viruses was safe. However, sublingual inoculation with a higher dose or tonsillar inoculation resulted in secondary oral lesions, indicating the need to optimize the dose and route for oral immunization with replication-competent vaccinia virus vectors. Oral priming alone elicited antibody responses to vaccinia virus and to the SF162 Env protein. Intramuscular immunization with the SF162 gp120 protein at either 20 or 21 weeks postpriming resulted in a significant boost in antibody responses in both systemic and mucosal compartments. Furthermore, we showed that immune responses induced by recombinant vaccinia virus priming and intramuscular protein boosting provided protection against intrarectal challenge with the simian-human immunodeficiency virus SHIV-SF162-P4.
[Mh] Termos MeSH primário: Vacinas contra a AIDS/imunologia
Anticorpos Anti-HIV/sangue
HIV-1/imunologia
Vacinas Sintéticas/imunologia
Vírus Vaccinia/imunologia
[Mh] Termos MeSH secundário: Vacinas contra a AIDS/efeitos adversos
Animais
Linhagem Celular
Cercopithecus aethiops
Proteínas de Fusão gag-pol/genética
Proteínas de Fusão gag-pol/imunologia
Proteína gp120 do Envelope de HIV/imunologia
Proteína gp160 do Envelope de HIV/imunologia
Imunidade nas Mucosas/imunologia
Imunoglobulina A/sangue
Imunoglobulina G/sangue
Macaca mulatta/imunologia
Vacinação
Vacinas Sintéticas/efeitos adversos
Vírus Vaccinia/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (AIDS Vaccines); 0 (Fusion Proteins, gag-pol); 0 (HIV Antibodies); 0 (HIV Envelope Protein gp120); 0 (HIV Envelope Protein gp160); 0 (Immunoglobulin A); 0 (Immunoglobulin G); 0 (Vaccines, Synthetic); 0 (gp120 protein, Human immunodeficiency virus 1); 0 (gp160 protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161231
[Lr] Data última revisão:
161231
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160101
[St] Status:MEDLINE
[do] DOI:10.1128/CVI.00597-15


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[PMID]:26382736
[Au] Autor:Green L; Goff SP
[Ti] Título:Translational readthrough-promoting drugs enhance pseudoknot-mediated suppression of the stop codon at the Moloney murine leukemia virus gag­pol junction.
[So] Source:J Gen Virol;96(11):3411-21, 2015 Nov.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Translational readthrough-promoting drugs enhance the incorporation of amino acids at stop codons and can thus bypass premature termination during protein synthesis. The polymerase (Pol) proteins of Moloney murine leukemia virus (MoMLV) are synthesized as a large Gag­Pol fusion protein, formed by the readthrough of a stop codon at the end of the gag ORF. The downstream pol ORF lacks its own start codon, and Pol protein synthesis is wholly dependent on translation of the upstream gag gene and the readthrough event for expression. Here, we explored the effects of readthrough-promoting drugs ­ aminoglycoside antibiotics and the small molecule ataluren ­ on the efficiency of readthrough of the stop codon in the context of the MoMLV genome. We showed that these compounds increased readthrough of the stop codon at the MoMLV gag­pol junction in vivo above the already high basal level and that the resulting elevated gag­pol readthrough had deleterious effects on virus replication. We also showed that readthrough efficiency could be driven to even higher levels in vitro, and that the combination of the small molecules and the RNA structure at the MoMLV stop codon could achieve extremely high readthrough efficiencies.
[Mh] Termos MeSH primário: Aminoglicosídeos/farmacologia
Proteínas de Fusão gag-pol/genética
Vírus da Leucemia Murina de Moloney/genética
Oxidiazóis/farmacologia
Biossíntese de Proteínas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Aminoglicosídeos/efeitos adversos
Animais
Linhagem Celular
Códon de Terminação
Proteínas de Fusão gag-pol/metabolismo
Regulação Viral da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos
Vírus da Leucemia Murina de Moloney/efeitos dos fármacos
Vírus da Leucemia Murina de Moloney/metabolismo
Oxidiazóis/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Codon, Terminator); 0 (Fusion Proteins, gag-pol); 0 (Oxadiazoles); K16AME9I3V (ataluren)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150919
[St] Status:MEDLINE


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[PMID]:26030443
[Au] Autor:Yu FH; Chou TA; Liao WH; Huang KJ; Wang CT
[Ad] Endereço:Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
[Ti] Título:Gag-Pol Transframe Domain p6* Is Essential for HIV-1 Protease-Mediated Virus Maturation.
[So] Source:PLoS One;10(6):e0127974, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 protease (PR) is encoded by pol, which is initially translated as a Pr160gag-pol polyprotein by a ribosomal frameshift event. Within Gag-Pol, truncated p6gag is replaced by a transframe domain (referred to as p6* or p6pol) located directly upstream of PR. p6* has been proposed as playing a role in modulating PR activation. Overlapping reading frames between p6* and p6gag present a challenge to researchers using genetic approaches to studying p6* biological functions. To determine the role of p6* in PR activation without affecting the gag reading frame, we constructed a series of Gag/Gag-Pol expression vectors by duplicating PR with or without p6* between PR pairs, and observed that PR duplication eliminated virus production due to significant Gag cleavage enhancement. This effect was mitigated when p6* was placed between the two PRs. Further, Gag cleavage enhancement was markedly reduced when either one of the two PRs was mutationally inactivated. Additional reduction in Gag cleavage efficiency was noted following the removal of p6* from between the two PRs. The insertion of a NC domain (wild-type or mutant) directly upstream of PR or p6*PR did not significantly improve Gag processing efficiency. With the exception of those containing p6* directly upstream of an active PR, all constructs were either noninfectious or weakly infectious. Our results suggest that (a) p6* is essential for triggering PR activation, (b) p6* has a role in preventing premature virus processing, and
[Mh] Termos MeSH primário: Proteínas de Fusão gag-pol/metabolismo
Protease de HIV/metabolismo
Protease de HIV/fisiologia
HIV-1/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Fusão gag-pol/química
Proteínas de Fusão gag-pol/genética
Protease de HIV/química
Produtos do Gene gag do Vírus da Imunodeficiência Humana/química
Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fusion Proteins, gag-pol); 0 (gag Gene Products, Human Immunodeficiency Virus); EC 3.4.23.- (HIV Protease); EC 3.4.23.- (p16 protease, Human immunodeficiency virus 1)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150610
[Lr] Data última revisão:
150610
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150602
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0127974


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[PMID]:25855816
[Au] Autor:Sherpa C; Rausch JW; Le Grice SF; Hammarskjold ML; Rekosh D
[Ad] Endereço:Myles H. Thaler Center for AIDS and Human Retrovirus Research, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
[Ti] Título:The HIV-1 Rev response element (RRE) adopts alternative conformations that promote different rates of virus replication.
[So] Source:Nucleic Acids Res;43(9):4676-86, 2015 May 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The HIV Rev protein forms a complex with a 351 nucleotide sequence present in unspliced and incompletely spliced human immunodeficiency virus (HIV) mRNAs, the Rev response element (RRE), to recruit the cellular nuclear export receptor Crm1 and Ran-GTP. This complex facilitates nucleo-cytoplasmic export of these mRNAs. The precise secondary structure of the HIV-1 RRE has been controversial, since studies have reported alternative structures comprising either four or five stem-loops. The published structures differ only in regions that lie outside of the primary Rev binding site. Using in-gel SHAPE, we have now determined that the wt NL4-3 RRE exists as a mixture of both structures. To assess functional differences between these RRE 'conformers', we created conformationally locked mutants by site-directed mutagenesis. Using subgenomic reporters, as well as HIV replication assays, we demonstrate that the five stem-loop form of the RRE promotes greater functional Rev/RRE activity compared to the four stem-loop counterpart.
[Mh] Termos MeSH primário: HIV-1/genética
RNA Viral/química
Sequências Reguladoras de Ácido Ribonucleico
Replicação Viral/genética
Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Fusão gag-pol/metabolismo
Genes env
HIV-1/fisiologia
Mutação
Conformação de Ácido Nucleico
RNA Viral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (Fusion Proteins, gag-pol); 0 (RNA, Viral); 0 (Regulatory Sequences, Ribonucleic Acid); 0 (rev Gene Products, Human Immunodeficiency Virus); 0 (rev protein, Human Immunodeficiency Virus-1)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150410
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkv313



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