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[PMID]:28961413
[Au] Autor:Faust TB; Binning JM; Gross JD; Frankel AD
[Ad] Endereço:Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158; email: tybifa@gmail.com , frankel@cgl.ucsf.edu.
[Ti] Título:Making Sense of Multifunctional Proteins: Human Immunodeficiency Virus Type 1 Accessory and Regulatory Proteins and Connections to Transcription.
[So] Source:Annu Rev Virol;4(1):241-260, 2017 Sep 29.
[Is] ISSN:2327-0578
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Viruses are completely dependent upon cellular machinery to support replication and have therefore developed strategies to co-opt cellular processes to optimize infection and counter host immune defenses. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode a relatively small number of genes. Viruses with limited genetic content often encode multifunctional proteins that function at multiple stages of the viral replication cycle. In this review, we discuss the functions of HIV-1 regulatory (Tat and Rev) and accessory (Vif, Vpr, Vpu, and Nef) proteins. Each of these proteins has a highly conserved primary activity; however, numerous additional activities have been attributed to these viral proteins. We explore the possibility that HIV-1 proteins leverage their multifunctional nature to alter host transcriptional networks to elicit a diverse set of cellular responses. Although these transcriptional effects appear to benefit the virus, it is not yet clear whether they are strongly selected for during viral evolution or are a ripple effect from the primary function. As our detailed knowledge of these viral proteins improves, we will undoubtedly uncover how the multifunctional nature of these HIV-1 regulatory and accessory proteins, and in particular their transcriptional functions, work to drive viral pathogenesis.
[Mh] Termos MeSH primário: Genes rev
Genes tat
HIV-1/genética
Proteínas do Vírus da Imunodeficiência Humana/metabolismo
Transcrição Genética
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Mh] Termos MeSH secundário: HIV-1/química
HIV-1/fisiologia
Interações Hospedeiro-Patógeno
Proteínas do Vírus da Imunodeficiência Humana/genética
Seres Humanos
Proteínas Virais Reguladoras e Acessórias/genética
Replicação Viral
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpu protein, Human immunodeficiency virus 1)
[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:170930
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-virology-101416-041654


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[PMID]:28754362
[Au] Autor:Pu C; Luo RH; Zhang M; Hou X; Yan G; Luo J; Zheng YT; Li R
[Ad] Endereço:Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041 Sichuan, PR China.
[Ti] Título:Design, synthesis and biological evaluation of indole derivatives as Vif inhibitors.
[So] Source:Bioorg Med Chem Lett;27(17):4150-4155, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The crystal structure of viral infectivity factor (Vif) was reported recently, which makes it possible to design new inhibitors against Vif by structure-based drug design. Through analysis of the protein surface of Vif, the C2 pocket located in the N-terminal was found, which is suit for developing small molecular inhibitors. Then, in our article, fragment-based virtual screening (FBVS) was conducted and a series of fragments was obtained, among which, Zif-1 bearing indole scaffold and pyridine ring can form H-bonds with Tyr148 and Ile155. Subsequently, 19 derivatives of Zif-1 were synthesized. Through the immune-fluorescence staining and Western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Further docking experiment shows that Zif-15 form H-bond interactions with residues His139, Tyr148 and Ile155. Therefore, Zif-15 is a promising lead compound against Vif that can be used to treat AIDS.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Desenho de Drogas
HIV-1/efeitos dos fármacos
Indóis/farmacologia
Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/síntese química
Fármacos Anti-HIV/química
Relação Dose-Resposta a Droga
Indóis/síntese química
Indóis/química
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Indoles); 0 (vif Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170730
[St] Status:MEDLINE


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[PMID]:28475648
[Au] Autor:Nakano Y; Misawa N; Juarez-Fernandez G; Moriwaki M; Nakaoka S; Funo T; Yamada E; Soper A; Yoshikawa R; Ebrahimi D; Tachiki Y; Iwami S; Harris RS; Koyanagi Y; Sato K
[Ad] Endereço:Laboratory of Systems Virology, Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
[Ti] Título:HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation.
[So] Source:PLoS Pathog;13(5):e1006348, 2017 May.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1.
[Mh] Termos MeSH primário: Aminoidrolases/genética
Citosina Desaminase/genética
Infecções por HIV/virologia
HIV-1/fisiologia
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Aminoidrolases/metabolismo
Animais
Citosina Desaminase/metabolismo
Modelos Animais de Doenças
Células HEK293
Infecções por HIV/transmissão
HIV-1/genética
Seres Humanos
Camundongos
Camundongos Knockout
Modelos Genéticos
Mutação
Filogenia
RNA Viral/química
RNA Viral/genética
Análise de Sequência de RNA
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Viral); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1); EC 3.5.4.- (APOBEC3H protein, human); EC 3.5.4.- (Aminohydrolases); EC 3.5.4.1 (APOBEC3 protein, human); EC 3.5.4.1 (Cytosine Deaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170506
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006348


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[PMID]:28446664
[Au] Autor:Brillen AL; Walotka L; Hillebrand F; Müller L; Widera M; Theiss S; Schaal H
[Ad] Endereço:Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
[Ti] Título:Analysis of Competing HIV-1 Splice Donor Sites Uncovers a Tight Cluster of Splicing Regulatory Elements within Exon 2/2b.
[So] Source:J Virol;91(14), 2017 Jul 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The HIV-1 accessory protein Vif is essential for viral replication by counteracting the host restriction factor APOBEC3G (A3G), and balanced levels of both proteins are required for efficient viral replication. Noncoding exons 2/2b contain the Vif start codon between their alternatively used splice donors 2 and 2b (D2 and D2b). For mRNA, intron 1 must be removed while intron 2 must be retained. Thus, splice acceptor 1 (A1) must be activated by U1 snRNP binding to either D2 or D2b, while splicing at D2 or D2b must be prevented. Here, we unravel the complex interactions between previously known and novel components of the splicing regulatory network regulating HIV-1 exon 2/2b inclusion in viral mRNAs. In particular, using RNA pulldown experiments and mass spectrometry analysis, we found members of the heterogeneous nuclear ribonucleoparticle (hnRNP) A/B family binding to a novel splicing regulatory element (SRE), the exonic splicing silencer ESS2b, and the splicing regulatory proteins Tra2/SRSF10 binding to the nearby exonic splicing enhancer ESE2b. Using a minigene reporter, we performed bioinformatics HEXplorer-guided mutational analysis to narrow down SRE motifs affecting splice site selection between D2 and D2b. Eventually, the impacts of these SREs on the viral splicing pattern and protein expression were exhaustively analyzed in viral particle production and replication experiments. Masking of these protein binding sites by use of locked nucleic acids (LNAs) impaired Vif expression and viral replication. Based on our results, we propose a model in which a dense network of SREs regulates mRNA and protein expression, crucial to maintain viral replication within host cells with varying A3G levels and at different stages of infection. This regulation is maintained by several serine/arginine-rich splicing factors (SRSF) and hnRNPs binding to those elements. Targeting this cluster of SREs with LNAs may lead to the development of novel effective therapeutic strategies.
[Mh] Termos MeSH primário: HIV-1/genética
Sítios de Splice de RNA
Fatores de Processamento de RNA/análise
RNA Viral/genética
Sequências Reguladoras de Ácido Ribonucleico
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Sítios de Ligação
Linhagem Celular
Centrifugação
Análise Mutacional de DNA
Éxons
Seres Humanos
Espectrometria de Massas
RNA Viral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA Splice Sites); 0 (RNA Splicing Factors); 0 (RNA, Viral); 0 (Regulatory Sequences, Ribonucleic Acid); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE


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[PMID]:28336404
[Au] Autor:Nakashima M; Tsuzuki S; Awazu H; Hamano A; Okada A; Ode H; Maejima M; Hachiya A; Yokomaku Y; Watanabe N; Akari H; Iwatani Y
[Ad] Endereço:Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.
[Ti] Título:Mapping Region of Human Restriction Factor APOBEC3H Critical for Interaction with HIV-1 Vif.
[So] Source:J Mol Biol;429(8):1262-1276, 2017 Apr 21.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The APOBEC3 (A3) family of cellular cytidine deaminases comprises seven members (A, B, C, D, F, G, and H) that potently inhibit retroviral replication. Human immunodeficiency virus type 1 (HIV-1) Vif is a small pleiotropic protein that specifically inactivates these enzymes, targeting them for ubiquitin-mediated proteasomal degradation. A3 Vif-interaction sites are presumed to fall into three distinct types: A3C/D/F, A3G, and A3H. To date, two types of A3G and A3C/D/F sites have been well characterized, whereas the A3H Vif-binding site remains poorly defined. Here, we explore the residues critical for the A3H-type Vif interaction. To avoid technical difficulties in performing experiments with human A3H haplotype II (hapII), which is relatively resistant to HIV-1 Vif, we employed its ortholog chimpanzee A3H (cA3H), which displays high Vif sensitivity, for a comparison of sensitivity with that of A3H hapII. The Vif susceptibility of A3H hapII-cA3H chimeras and their substitution mutants revealed a single residue at position 97 as a major determinant for the difference in their Vif sensitivities. We further surveyed critical residues by structure-guided mutagenesis using an A3H structural model and thus identified eight additional residues important for Vif sensitivity, which mapped to the α3 and α4 helices of A3H. Interestingly, this area is located on a surface adjacent to the A3G and A3C/D/F interfaces and is composed of negatively charged and hydrophobic patches. These findings suggest that HIV-1 Vif has evolved to utilize three dispersed surfaces for recognizing three types of interfaces on A3 proteins under certain structural constraints.
[Mh] Termos MeSH primário: Aminoidrolases/metabolismo
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Aminoidrolases/química
Aminoidrolases/genética
Animais
Sítios de Ligação
Interações Hospedeiro-Patógeno
Seres Humanos
Mutagênese
Pan troglodytes
Conformação Proteica
Mapeamento de Interação de Proteínas/métodos
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1); EC 3.5.4.- (APOBEC3H protein, human); EC 3.5.4.- (Aminohydrolases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170427
[Lr] Data última revisão:
170427
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE


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[PMID]:28315663
[Au] Autor:Jaguva Vasudevan AA; Hofmann H; Willbold D; Häussinger D; Koenig BW; Münk C
[Ad] Endereço:Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
[Ti] Título:Enhancing the Catalytic Deamination Activity of APOBEC3C Is Insufficient to Inhibit Vif-Deficient HIV-1.
[So] Source:J Mol Biol;429(8):1171-1191, 2017 Apr 21.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The retroviral restriction factors of the APOBEC3 (A3) cytidine deaminase family catalyze the deamination of cytidines in single-stranded viral DNA. APOBEC3C (A3C) is a strong antiviral factor against viral infectivity factor (vif)-deficient simian immunodeficiency virus Δvif, which is, however, a weak inhibitor against human immunodeficiency virus (HIV)-1 for reasons unknown. The precise link between the antiretroviral effect of A3C and its catalytic activity is incompletely understood. Here, we show that the S61P mutation in human A3C (A3C.S61P) boosted hypermutation in the viral genomes of simian immunodeficiency virus Δvif and murine leukemia virus but not in human immunodeficiency virus HIV-1Δvif. The enhanced antiviral activity of A3C.S61P correlated with enhanced in vitro cytidine deamination. Furthermore, the S61P mutation did not change the substrate specificity of A3C, ribonucleoprotein complex formation, self-association, Zinc coordination, or viral incorporation features. We propose that local structural changes induced by the serine-to-proline substitution are responsible for the gain of catalytic activity of A3C.S61P. Our results are a first step toward an understanding of A3C's DNA binding capacity, deamination-dependent editing, and antiviral functions at the molecular level. We conclude that the enhanced enzymatic activity of A3C is insufficient to restrict HIV-1, indicating an unknown escape mechanism of HIV-1.
[Mh] Termos MeSH primário: Citidina Desaminase/química
Citidina Desaminase/metabolismo
HIV-1/patogenicidade
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Citidina Desaminase/genética
Citosina/metabolismo
DNA de Cadeia Simples/química
DNA de Cadeia Simples/metabolismo
DNA Viral/metabolismo
Células HEK293/virologia
HIV-1/genética
Interações Hospedeiro-Patógeno
Seres Humanos
Vírus da Leucemia Murina/metabolismo
Vírus da Leucemia Murina/patogenicidade
Pan troglodytes
Conformação Proteica
Vírus da Imunodeficiência Símia/metabolismo
Vírus da Imunodeficiência Símia/patogenicidade
Zinco/metabolismo
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Single-Stranded); 0 (DNA, Viral); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1); 8J337D1HZY (Cytosine); EC 3.5.4.5 (APOBEC3C protein, human); EC 3.5.4.5 (Cytidine Deaminase); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170427
[Lr] Data última revisão:
170427
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170320
[St] Status:MEDLINE


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[PMID]:28302150
[Au] Autor:Desimmie BA; Smith JL; Matsuo H; Hu WS; Pathak VK
[Ad] Endereço:Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA.
[Ti] Título:Identification of a tripartite interaction between the N-terminus of HIV-1 Vif and CBFß that is critical for Vif function.
[So] Source:Retrovirology;14(1):19, 2017 Mar 17.
[Is] ISSN:1742-4690
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: HIV-1 Vif interacts with the cellular core-binding factor ß (CBFß) and counteracts the protective roles of certain human APOBEC3 (A3) proteins by targeting them for proteasomal degradation. Previous studies have identified some amino acids important for Vif-CBFß interactions, and recently a co-crystal structure of a pentameric complex of HIV-1 Vif, CBFß, Cul5, EloB, and EloC was resolved. However, a comprehensive analysis of Vif-CBFß interactions that are important for Vif function has not been performed. RESULTS: Here, we carried out double-alanine scanning mutagenesis of the first 60 amino acids of Vif and determined their effects on interaction with CBFß and their ability to induce A3G degradation as well as rescue HIV-1 replication in the presence of A3G. We found that multiple Vif residues are involved in the extensive N-terminal Vif-CBFß interaction and that the WQVMIVW region of Vif is the major determinant. A minimum of three alanine substitutions are required to completely abrogate the Vif-CBFß interaction and Vif's ability to rescue HIV-1 infectivity in the presence of A3G. Mutational analysis of CBFß revealed that F68 and I55 residues are important and participate in a tripartite hydrophobic interaction with W5 of Vif to maintain a stable and functional Vif-CBFß complex. We also determined that CBFß amino acids WQGEQR , which are not resolved in the structure of the pentameric complex, are not involved in interaction with HIV-1 Vif. CONCLUSIONS: Our results provide detailed insight into the Vif-CBFß interactions that are critical for Vif function and may contribute to the rational design of HIV-1 inhibitors that block Vif-mediated degradation of A3 proteins.
[Mh] Termos MeSH primário: Subunidade beta de Fator de Ligação ao Core/metabolismo
HIV-1/fisiologia
Interações Hospedeiro-Patógeno
Mapeamento de Interação de Proteínas
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Subunidade beta de Fator de Ligação ao Core/genética
Análise Mutacional de DNA
Seres Humanos
Mutagênese Sítio-Dirigida
Ligação Proteica
Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CBFB protein, human); 0 (Core Binding Factor beta Subunit); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1)
[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:170318
[St] Status:MEDLINE
[do] DOI:10.1186/s12977-017-0346-5


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[PMID]:28299671
[Au] Autor:Kim DY; Gross JD
[Ad] Endereço:College of Pharmacy, Yeungnam University, Gyeongsan, 38541, South Korea.
[Ti] Título:CBFß and HIV Infection.
[So] Source:Adv Exp Med Biol;962:415-431, 2017.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In order to achieve a persistent infection, viruses must overcome the host immune system. Host restriction factors dominantly block virus transmission, but are subject to down regulation by viral accessory proteins. HIV encodes several accessory factors that overcome different cellular restriction factors. For example, the HIV-1 protein Vif down regulates the human APOBEC3 family of restriction factors by targeting them for proteolysis by the ubiquitin-proteasome pathway. Recently, this function was shown to require the transcription cofactor CBFß, which acts as a template to assist in Vif folding and allow for assembly of an APOBEC3-targeting E3 ligase complex. In uninfected cells, CBFß is an essential binding partner of RUNX transcription factors. By binding CBFß, Vif has also been shown to perturb transcription of genes regulated by the RUNX proteins, including restrictive APOBEC3 family members. Here we review how the link between CBFß and Vif supports transcriptional and post-transcriptional repression of innate immunity. The ability of a single viral protein to coopt multiple host pathways is an economical strategy for a pathogen with limited protein coding capacity to achieve a productive infection.
[Mh] Termos MeSH primário: Subunidade beta de Fator de Ligação ao Core/metabolismo
Infecções por HIV/metabolismo
Infecções por HIV/virologia
HIV-1/metabolismo
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Animais
Subunidade beta de Fator de Ligação ao Core/imunologia
Citosina Desaminase/imunologia
Citosina Desaminase/metabolismo
Infecções por HIV/imunologia
HIV-1/imunologia
Interações Hospedeiro-Patógeno/imunologia
Interações Hospedeiro-Patógeno/fisiologia
Seres Humanos
Imunidade Inata/imunologia
Transcrição Genética/imunologia
Transcrição Genética/fisiologia
Produtos do Gene vif do Vírus da Imunodeficiência Humana/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Core Binding Factor beta Subunit); 0 (vif Gene Products, Human Immunodeficiency Virus); EC 3.5.4.1 (Cytosine Deaminase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1007/978-981-10-3233-2_25


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[PMID]:28235704
[Au] Autor:Zhou M; Luo RH; Hou XY; Wang RR; Yan GY; Chen H; Zhang RH; Shi JY; Zheng YT; Li R; Wei YQ
[Ad] Endereço:State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China; Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guizhou Medical Uni
[Ti] Título:Synthesis, biological evaluation and molecular docking study of N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif antagonists.
[So] Source:Eur J Med Chem;129:310-324, 2017 Mar 31.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), we found a potent compound 12c with EC value of 1.54 µM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1 , HIV-1 and HIV-1 ) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a, improving the water solubility about 2600-fold compared with 12c. Moreover, 13a inhibited the virus replication efficiently with an EC value of 0.228 µM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/síntese química
Benzamidas/farmacologia
Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores
[Mh] Termos MeSH secundário: Desaminase APOBEC-3G/metabolismo
Fármacos Anti-HIV/farmacologia
Benzamidas/síntese química
Linhagem Celular
Farmacorresistência Viral
Seres Humanos
Simulação de Acoplamento Molecular
Pró-Fármacos/síntese química
Pró-Fármacos/farmacocinética
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Benzamides); 0 (Prodrugs); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1); EC 3.5.4.5 (APOBEC-3G Deaminase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170309
[Lr] Data última revisão:
170309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE


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[PMID]:28184007
[Au] Autor:Augustine T; Chaudhary P; Gupta K; Islam S; Ghosh P; Santra MK; Mitra D
[Ad] Endereço:From the National Centre for Cell Science, Pune, Maharashtra 411007, India and.
[Ti] Título:Cyclin F/FBXO1 Interacts with HIV-1 Viral Infectivity Factor (Vif) and Restricts Progeny Virion Infectivity by Ubiquitination and Proteasomal Degradation of Vif Protein through SCF E3 Ligase Machinery.
[So] Source:J Biol Chem;292(13):5349-5363, 2017 Mar 31.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cyclin F protein, also known as FBXO1, is the largest among all cyclins and oscillates in the cell cycle like other cyclins. Apart from being a G /M cyclin, cyclin F functions as the substrate-binding subunit of SCF E3 ubiquitin ligase. In a gene expression analysis performed to identify novel gene modulations associated with cell cycle dysregulation during HIV-1 infection in CD4 T cells, we observed down-regulation of the cyclin F gene ( ). Later, using gene overexpression and knockdown studies, we identified cyclin F as negatively influencing HIV-1 viral infectivity without any significant impact on virus production. Subsequently, we found that cyclin F negatively regulates the expression of viral protein Vif (viral infectivity factor) at the protein level. We also identified a novel host-pathogen interaction between cyclin F and Vif protein in T cells during HIV-1 infection. Mutational analysis of a cyclin F-specific amino acid motif in the C-terminal region of Vif indicated rescue of the protein from cyclin F-mediated down-regulation. Subsequently, we showed that Vif is a novel substrate of the SCF E3 ligase, where cyclin F mediates the ubiquitination and proteasomal degradation of Vif through physical interaction. Finally, we showed that cyclin F augments APOBEC3G expression through degradation of Vif to regulate infectivity of progeny virions. Taken together, our results demonstrate that cyclin F is a novel F-box protein that functions as an intrinsic cellular regulator of HIV-1 Vif and has a negative regulatory effect on the maintenance of viral infectivity by restoring APOBEC3G expression.
[Mh] Termos MeSH primário: Ciclinas/fisiologia
Complexo de Endopeptidases do Proteassoma/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Ubiquitinação
Vírion/patogenicidade
Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Desaminase APOBEC-3G/metabolismo
Linfócitos T CD4-Positivos
Células Cultivadas
Ciclinas/genética
Ciclinas/metabolismo
Proteínas F-Box
Perfilação da Expressão Gênica
Regulação Viral da Expressão Gênica
Seres Humanos
Processamento de Proteína Pós-Traducional
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCNF protein, human); 0 (Cyclins); 0 (F-Box Proteins); 0 (vif Gene Products, Human Immunodeficiency Virus); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.5.4.5 (APOBEC-3G Deaminase); EC 3.5.4.5 (APOBEC3G protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170612
[Lr] Data última revisão:
170612
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.765842



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