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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]:28424288
[Au] Autor:Miller CM; Akiyama H; Agosto LM; Emery A; Ettinger CR; Swanstrom RI; Henderson AJ; Gummuluru S
[Ad] Endereço:Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
[Ti] Título:Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells.
[So] Source:J Virol;91(13), 2017 Jul 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr for facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cell types to encounter virus in the peripheral mucosal tissues. In this report, we characterize a significant restriction of Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC-CD4 T cell cocultures. This restriction of HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by the expression of Vpr in in the incoming virion. Interestingly, infections of MDDCs with viruses that encode Vpr mutants unable to interact with either the DCAF1/DDB1 E3 ubiquitin ligase complex or a host factor hypothesized to be targeted for degradation by Vpr also displayed a significant replication defect. While the extent of proviral integration in HIV-1-infected MDDCs was unaffected by the absence of Vpr, the transcriptional activity of the viral long terminal repeat (LTR) from Vpr-deficient proviruses was significantly reduced. Together, these results characterize a novel postintegration restriction of HIV-1 replication in MDDCs and show that the interaction of Vpr with the DCAF1/DDB1 E3 ubiquitin ligase complex and the yet-to-be-identified host factor might alleviate this restriction by inducing transcription from the viral LTR. Taken together, these findings identify a robust cell culture system that is amenable to addressing mechanisms underlying Vpr-mediated enhancement of HIV-1 replication. Despite decades of work, the function of the HIV-1 protein Vpr remains poorly understood, primarily due to the lack of an cell culture system that demonstrates a deficit in replication upon infection with viruses in the absence of Vpr. In this report, we describe a novel cell infection system that utilizes primary human dendritic cells, which display a robust decrease in viral replication upon infection with Vpr-deficient HIV-1. We show that this replication difference occurs in a single round of infection and is due to decreased transcriptional output from the integrated viral genome. Viral transcription could be rescued by virion-associated Vpr. Using mutational analysis, we show that domains of Vpr involved in binding to the DCAF1/DDB1/E3 ubiquitin ligase complex and prevention of cell cycle progression into mitosis are required for LTR-mediated viral expression, suggesting that the evolutionarily conserved G cell cycle arrest function of Vpr is essential for HIV-1 replication.
[Mh] Termos MeSH primário: Células Dendríticas/virologia
HIV-1/crescimento & desenvolvimento
Interações Hospedeiro-Patógeno
Integração Viral
Replicação Viral
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Transporte
Células Cultivadas
Técnicas de Cocultura
HIV-1/fisiologia
Seres Humanos
Linfócitos T/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (VprBP protein, human); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE


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[PMID]:28202763
[Au] Autor:Wang H; Guo H; Su J; Rui Y; Zheng W; Gao W; Zhang W; Li Z; Liu G; Markham RB; Wei W; Yu XF
[Ad] Endereço:School of Life Science, Tianjin University, Tianjin, China.
[Ti] Título:Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly.
[So] Source:J Virol;91(9), 2017 May 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or host helicase transcription factor (HLTF), respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that posttranslational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood. Here, we report that zinc coordination is an important regulator of Vpx-CRL4 E3 ligase assembly. Residues in a conserved zinc-binding motif of Vpx were essential for the recruitment of the CRL4 (DCAF1) E3 complex and Vpx-induced SAMHD1 degradation. Importantly, altering the intracellular zinc concentration by treatment with the zinc chelator , , '-tetrakis-(2'-pyridylmethyl)ethylenediamine (TPEN) potently blocked Vpx-mediated SAMHD1 degradation and inhibited wild-type SIVmac (simian immunodeficiency virus of macaques) infection of myeloid cells, even in the presence of Vpx. TPEN selectively inhibited Vpx and DCAF1 binding but not the Vpx-SAMHD1 interaction or Vpx virion packaging. Moreover, we have shown that zinc coordination is also important for the assembly of the HIV-1 Vpr-CRL4 E3 ligase. In particular, Vpr zinc-binding motif mutation or TPEN treatment efficiently inhibited Vpr-CRL4 (DCAF1) E3 ligase assembly and Vpr-mediated HLTF degradation or Vpr-induced G cell cycle arrest. Collectively, our study sheds light on a conserved strategy by the viral proteins Vpx and Vpr to recruit host CRL4 (DCAF1) E3 ligase, which represents a target for novel anti-human immunodeficiency virus (HIV) drug development. The Vpr and its paralog Vpx are accessory proteins encoded by different human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) lentiviruses. To facilitate viral replication, Vpx has evolved to induce SAMHD1 degradation and Vpr to mediate HLTF degradation. Both Vpx and Vpr perform their functions by recruiting CRL4 (DCAF1) E3 ligase. In this study, we demonstrate that the assembly of the Vpx- or Vpr-CRL4 E3 ligase requires a highly conserved zinc-binding motif. This motif is specifically required for the DCAF1 interaction but not for the interaction of Vpx or Vpr with its substrate. Selective disruption of Vpx- or Vpr-CRL4 E3 ligase function was achieved by zinc sequestration using , , '-tetrakis-(2'-pyridylmethyl)ethylenediamine (TPEN). At the same time, zinc sequestration had no effect on zinc-dependent cellular protein functions. Therefore, information obtained from this study may be important for novel anti-HIV drug development.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Proteínas Monoméricas de Ligação ao GTP/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Proteínas Virais Reguladoras e Acessórias/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Proteínas de Ligação a DNA/metabolismo
Etilenodiaminas/farmacologia
Pontos de Checagem da Fase G2 do Ciclo Celular
Células HEK293
Infecções por HIV/virologia
HIV-1/metabolismo
Interações Hospedeiro-Patógeno
Seres Humanos
Células Mieloides/virologia
Estrutura Terciária de Proteína
Proteína 1 com Domínio SAM e Domínio HD
Vírus da Imunodeficiência Símia/metabolismo
Fatores de Transcrição/metabolismo
Proteínas Virais Reguladoras e Acessórias/genética
Replicação Viral
Zinco/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (DNA-Binding Proteins); 0 (Ethylenediamines); 0 (HLTF protein, human); 0 (Transcription Factors); 0 (VPX protein, Simian immunodeficiency virus); 0 (Viral Regulatory and Accessory Proteins); 0 (VprBP protein, human); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.1.5.- (SAM Domain and HD Domain-Containing Protein 1); EC 3.1.5.- (SAMHD1 protein, human); EC 3.6.5.2 (Monomeric GTP-Binding Proteins); EC 6.3.2.- (CRL4 protein, human); J41CSQ7QDS (Zinc); R9PTU1U29I (N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE


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[PMID]:28075409
[Au] Autor:González ME
[Ad] Endereço:Unidad de Expresión Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera de Majadahonda-Pozuelo Km 2, Majadahonda, 28220 Madrid, Spain. megonzalez@isciii.es.
[Ti] Título:The HIV-1 Vpr Protein: A Multifaceted Target for Therapeutic Intervention.
[So] Source:Int J Mol Sci;18(1), 2017 Jan 10.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The human immunodeficiency virus type 1 (HIV-1) Vpr protein is an attractive target for antiretroviral drug development. The conservation both of the structure along virus evolution and the amino acid sequence in viral isolates from patients underlines the importance of Vpr for the establishment and progression of HIV-1 disease. While its contribution to virus replication in dividing and non-dividing cells and to the pathogenesis of HIV-1 in many different cell types, both extracellular and intracellular forms, have been extensively studied, its precise mechanism of action nevertheless remains enigmatic. The present review discusses how the apparently multifaceted interplay between Vpr and host cells may be due to the impairment of basic metabolic pathways. Vpr protein modifies host cell energy metabolism, oxidative status, and proteasome function, all of which are likely conditioned by the concentration and multimerization of the protein. The characterization of Vpr domains along with new laboratory tools for the assessment of their function has become increasingly relevant in recent years. With these advances, it is conceivable that drug discovery efforts involving Vpr-targeted antiretrovirals will experience substantial growth in the coming years.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Infecções por HIV/etiologia
HIV-1/efeitos dos fármacos
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Fármacos Anti-HIV/uso terapêutico
Proteínas de Transporte/metabolismo
Sequência Conservada
Progressão da Doença
Descoberta de Drogas
Evolução Molecular
Infecções por HIV/tratamento farmacológico
Infecções por HIV/metabolismo
HIV-1/fisiologia
Seres Humanos
Lentivirus de Primatas/genética
Ligação Proteica
Replicação Viral
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/química
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Carrier Proteins); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE


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[PMID]:28057470
[Au] Autor:Zhou HY; Zheng YH; He Y; Chen Z; He B
[Ad] Endereço:Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. Electronic address: zhouhuaying_2004@126.com.
[Ti] Título:The role of autophagy in THP-1 macrophages resistance to HIV- vpr-induced apoptosis.
[So] Source:Exp Cell Res;351(1):68-73, 2017 Feb 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Macrophages are resistant to cell death and are one of HIV reservoirs. HIV viral protein Vpr has the potential to promote infection of and survival of macrophages, which could be a highly significant factor in the development and/or maintenance of macrophage viral reservoirs. However, the impact of vpr on macrophages resistance to apoptosis is yet to be comprehended. Autophagy is a cell survival mechanism under stress state. In this study, we investigated whether autophagy is involved in macrophages resistant to vpr-induced apoptosis. Using the THP1 macrophages, we studied the interconnection between macrophages resistance to apoptosis and autophagy. We found that vpr is able to trigger autophagy in transfected THP-1 macrophages confirmed by electron microscopy (EM) and western blot analysis, and inhibition of autophagy with 3MA increased vpr-induced apoptosis. The results indicate that autophagy may be responsible for maintenance of macrophage HIV reservoirs.
[Mh] Termos MeSH primário: Apoptose
Autofagia
Macrófagos/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Macrófagos/ultraestrutura
Macrófagos/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (vpr Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170518
[Lr] Data última revisão:
170518
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE


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[PMID]:27328918
[Au] Autor:Kamori D; Hasan Z; Ohashi J; Kawana-Tachikawa A; Gatanaga H; Oka S; Ueno T
[Ad] Endereço:Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
[Ti] Título:Identification of two unique naturally occurring Vpr sequence polymorphisms associated with clinical parameters in HIV-1 chronic infection.
[So] Source:J Med Virol;89(1):123-129, 2017 Jan.
[Is] ISSN:1096-9071
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 viral protein R (Vpr) plays important roles in HIV-1 replication. Despite the identification of a number of HLA class I-associated immune escape mutations; it is yet known whether immune-driven Vpr polymorphisms are associated with disease outcome. Hereby, we comprehensively analyzed Vpr sequence polymorphisms and their association with disease outcome and host HLA genotypes, by using plasma viral RNA isolated from 444 HLA-typed, treatment-naïve, chronically HIV-1 infected individuals. Vpr amino acid residues at positions 13, 37, 45, 55, 63, 77, 84, 85, 86, and 93 were significantly associated with patients' plasma viral load and/or CD4 count. Further analysis revealed Ala at position 55 was significantly associated with lower plasma viral load; and Thr at position 63 was significantly associated with lower plasma viral load and higher CD4 count. Also, the number of amino acid residues at the two positions, located in a functionally important α-helical domain, correlated inversely with plasma viral load and positively with CD4 count. Moreover, a phylogenetically corrected method revealed residues at positions 55 and 63 are associated with patients' HLA genotypes. Taken together, our results suggest that Vpr polymorphisms at functionally important and immune-reactive sites may contribute, at least in part, to viral replication and disease outcome in vivo. J. Med. Virol. 89:123-129, 2017. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Genótipo
Infecções por HIV/patologia
Infecções por HIV/virologia
HIV-1/classificação
HIV-1/genética
Polimorfismo Genético
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Adulto
Contagem de Linfócito CD4
Feminino
HIV-1/isolamento & purificação
Antígenos HLA/genética
Seres Humanos
Masculino
Resultado do Tratamento
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HLA Antigens); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160623
[St] Status:MEDLINE
[do] DOI:10.1002/jmv.24612


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[PMID]:28484185
[Au] Autor:Sato K
[Ad] Endereço:Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University.
[Ti] Título:Investigation of HIV-1 pathogenesis using humanized mouse model.
[So] Source:Uirusu;66(1):91-100, 2016.
[Is] ISSN:0042-6857
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, is a human-speci virus. Because HIV-1 cannot infect and cause disorders in other animals, it has been an arduous struggle to investigate the dynamics of HIV-1 infection in vivo. In order to understand and elucidate HIV-1 pathogenesis in vivo, we have established a human hematopoietic stem cell-transplanted "humanized" mouse model, which has the potential to maintain human hematopoiesis including human CD4-positive leukocytes under a physiological condition. In HIV-1-infected humanized mice, we reproduced HIV-1 pathogenesis including the gradual decline of peripheral CD4-positive T cells and immune activation.HIV-1 encodes four "accessory" genes, Vif, Vpu, Vpr, and Nef. It is known that these accessory genes are occasionally crucial for viral replication in in vitro cell culture system. However, since there were no adequate animal models for HIV-1 infection, the roles of these HIV-1 accessory genes in viral infection, replication, and pathogenesis in vivo remain unclear. By utilizing humanized mouse model and a series of mutated HIV-1, we have revealed that these viral accessory proteins potently promote viral replication by antagonizing/degrading anti-viral cellular proteins or exploiting a unique subset of human CD4-positive T cells.In this paper, I introduce the findings in HIV-1-infected humanized mouse model particularly focusing on the roles of HIV-1 accessory proteins in viral replication in vivo.
[Mh] Termos MeSH primário: Síndrome de Imunodeficiência Adquirida/virologia
Modelos Animais de Doenças
HIV-1/genética
HIV-1/patogenicidade
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD4-Positivos
HIV-1/fisiologia
Transplante de Células-Tronco Hematopoéticas
Proteínas do Vírus da Imunodeficiência Humana
Seres Humanos
Camundongos
Proteínas Virais Reguladoras e Acessórias
Virulência/genética
Replicação Viral/genética
Produtos do Gene nef do Vírus da Imunodeficiência Humana
Produtos do Gene vif do Vírus da Imunodeficiência Humana
Produtos do Gene vpr do Vírus da Imunodeficiência Humana
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1); 0 (vif Gene Products, Human Immunodeficiency Virus); 0 (vif protein, Human immunodeficiency virus 1); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1); 0 (vpu protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.2222/jsv.66.91


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[PMID]:27899251
[Au] Autor:Fan LQ; Du GX; Li PF; Li MW; Sun Y; Zhao LM
[Ad] Endereço:State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China. Electronic address: fanglq@ecust.edu.cn.
[Ti] Título:Improved breast cancer cell-specific intracellular drug delivery and therapeutic efficacy by coupling decoration with cell penetrating peptide and SP90 peptide.
[So] Source:Biomed Pharmacother;84:1783-1791, 2016 Dec.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Lack of satisfactory specificity towards tumor cells and poor intracellular delivery efficacy are the major drawbacks with conventional cancer chemotherapy. Conjugated anticancer drugs to targeting moieties e.g. to peptides with the ability to recognize cancer cells and to cell penetrating peptide can improve these characteristics, respectively. Combining a tumor homing peptide with an appropriate cell-penetrating peptide can enhance the tumor-selective internalization efficacy of the carrying cargo molecules. In the present study, the breast cancer homing ability of SP90 peptide and the synergistic effect of SP90 with a cell-penetrating peptide(C peptide) were evaluated. SP90 and chimeric peptide SP90-C specifically targeted cargo molecule into breast cancer cells, especially triple negative MDA-MB-231 cell, in a dose- and time-dependent manner, but not normal breast cells and other cancer cells, while C peptide alone had no cell-selectivity. SP90-C increased the intracellular delivery efficiency by 12-fold or 10-fold compared to SP90 or C peptide alone, respectively. SP90 and SP90-C conjugation increased the anti-proliferative and apoptosis-inducing activity of HIV-1 Vpr, a potential novel anticancer protein drug, to breast cancer cell but not normal breast cell by arresting cells in G2/M phase. With excellent breast cancer cell-selective penetrating efficacy, SP90-C appears as a promising candidate vector for targeted anti-cancer drug delivery. SP90-VPR-C is a potential novel breast cancer-targeted anticancer agent for its high anti-tumor activity and low toxicity.
[Mh] Termos MeSH primário: Antineoplásicos/metabolismo
Neoplasias da Mama/metabolismo
Peptídeos Penetradores de Células/metabolismo
Portadores de Fármacos
Sistemas de Liberação de Medicamentos/métodos
Oligopeptídeos/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/patologia
Proliferação Celular/efeitos dos fármacos
Peptídeos Penetradores de Células/química
Relação Dose-Resposta a Droga
Composição de Medicamentos
Feminino
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Seres Humanos
Células MCF-7
Oligopeptídeos/química
Proteínas Recombinantes de Fusão/metabolismo
Fatores de Tempo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/química
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cell-Penetrating Peptides); 0 (Drug Carriers); 0 (Oligopeptides); 0 (Recombinant Fusion Proteins); 0 (SP90 peptide); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161201
[St] Status:MEDLINE


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[PMID]:27648839
[Au] Autor:Chutiwitoonchai N; Siarot L; Takeda E; Shioda T; Ueda M; Aida Y
[Ad] Endereço:Viral Infectious Diseases Unit, RIKEN, Wako, Saitama, Japan.
[Ti] Título:HIV-1 Vpr Abrogates the Effect of TSG101 Overexpression to Support Virus Release.
[So] Source:PLoS One;11(9):e0163100, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 budding requires interaction between Gag and cellular TSG101 to initiate viral particle assembly and release via the endosomal sorting complexes required for transport (ESCRT) pathway. However, some reports show that overexpression of TSG101 inhibits virus release by disruption of Gag targeting process. Since a HIV-1 accessory protein, Vpr binds to Gag p6 domain at the position close to the binding site for TSG101, whether Vpr implicates TSG101 overexpression effect has not been investigated. Here, we found that Vpr abrogates TSG101 overexpression effect to rescue viral production. Co-transfection of TSG101 and Gag with Vpr prevented TSG101-induced Gag accumulation in endosomes and lysosomes. In addition, Vpr rescued virus-like particle (VLP) production in a similar manner as a lysosomal inhibitor, Bafilomycin A1 indicating that Vpr inhibits TSG101-induced Gag downregulation via lysosomal pathway. Vpr and Gag interaction is required to counteract TSG101 overexpression effect since Vpr A30F mutant which is unable to interact with Gag and incorporate into virions, reduced ability to prevent Gag accumulation and to rescue VLP production. In addition, GST pull-down assays and Biacore analysis revealed that Vpr competed with TSG101 for Gag binding. These results indicate that Vpr overcomes the effects of TSG101 overexpression to support viral production by competing with TSG101 to bind Gag.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/metabolismo
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo
Produtos do Gene gag/metabolismo
HIV-1/fisiologia
Fatores de Transcrição/metabolismo
Liberação de Vírus/fisiologia
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Proteínas de Ligação a DNA/genética
Complexos Endossomais de Distribuição Requeridos para Transporte/genética
Endossomos/metabolismo
Transferência Ressonante de Energia de Fluorescência
Produtos do Gene gag/genética
Células HEK293
HIV-1/genética
HIV-1/metabolismo
Células HeLa
Seres Humanos
Lisossomos/metabolismo
Microscopia de Fluorescência/métodos
Mutação
Ligação Proteica
Fatores de Transcrição/genética
Vírion/genética
Vírion/metabolismo
Vírion/fisiologia
Montagem de Vírus/genética
Liberação de Vírus/genética
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Endosomal Sorting Complexes Required for Transport); 0 (Gene Products, gag); 0 (Transcription Factors); 0 (Tsg101 protein); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170815
[Lr] Data última revisão:
170815
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0163100


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[PMID]:27624129
[Au] Autor:Fregoso OI; Emerman M
[Ad] Endereço:Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA ofregoso@mednet.ucla.edu memerman@fredhutch.org.
[Ti] Título:Activation of the DNA Damage Response Is a Conserved Function of HIV-1 and HIV-2 Vpr That Is Independent of SLX4 Recruitment.
[So] Source:MBio;7(5), 2016 Sep 13.
[Is] ISSN:2150-7511
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: There has been extraordinary progress in understanding the roles of lentiviral accessory proteins in antagonizing host antiviral defense proteins. However, the precise primary function of the accessory gene Vpr remains elusive. Here we suggest that engagement with the DNA damage response is an important function of primate lentiviral Vpr proteins because of its conserved function among diverse lentiviral lineages. In contrast, we show that, for HIV-1, HIV-2, and related Vpr isolates and orthologs, there is a lack of correlation between DNA damage response activation and interaction with the host SLX4 protein complex of structure specific endonucleases; some Vpr proteins are able to interact with SLX4, but the majority are not. Using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 method to knock out SLX4, we formally showed that HIV-1 and HIV-2 Vpr orthologs can still activate the DNA damage response and cell cycle arrest in the absence of SLX4. Together, our data suggest that activation of the DNA damage response, but not SLX4 interaction, is conserved and therefore indicative of an important function of Vpr. Our data also indicate that Vpr activates the DNA damage response through an SLX4-independent mechanism that remains uncharacterized. IMPORTANCE: HIV-1 and HIV-2 belong to a family of viruses called lentiviruses that infect at least 40 primate species, including humans. Lentiviruses have been circulating in primates for at least 5 million years. In order to better fight HIV, we must understand the viral and host factors necessary for infection, adaptation, and transmission of these viruses. Using the natural variation of HIV-1, HIV-2, and related lentiviruses, we have investigated the role of the DNA damage response in the viral life cycle. We have found that the ability of lentiviruses to activate the DNA damage response is largely conserved. However, we also found that the SLX4 host factor is not required for this activation, as was previously proposed. This indicates that the DNA damage response is an important player in the viral life cycle, and yet the mechanism(s) by which HIV-1, HIV-2, and other primate lentiviruses engage the DNA damage response is still unknown.
[Mh] Termos MeSH primário: Pontos de Checagem do Ciclo Celular
Dano ao DNA
HIV-1/fisiologia
HIV-2/fisiologia
Recombinases/metabolismo
Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Técnicas de Inativação de Genes
Interações Hospedeiro-Patógeno
Seres Humanos
Recombinases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinases); 0 (vpr Gene Products, Human Immunodeficiency Virus); 0 (vpr protein, Human immunodeficiency virus 1); 0 (vpr protein, Human immunodeficiency virus 2); EC 3.1.- (SLX4 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170622
[Lr] Data última revisão:
170622
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160915
[St] Status:MEDLINE



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