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[PMID]: 27771962 [Au] Autor: Fink E; Fuller K; Agan B; Berger EA; Saphire A; Quinnan GV; Elder JH [Ad] Endereço: 1 Department of Immunology and Microbial Science, The Scripps Research Institute , La Jolla, California. [Ti] Título: Humoral Antibody Responses to HIV Viral Proteins and to CD4 Among HIV Controllers, Rapid and Typical Progressors in an HIV-Positive Patient Cohort. [So] Source: AIDS Res Hum Retroviruses;32(12):1187-1197, 2016 12. [Is] ISSN: 1931-8405 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The purpose of this study was to assess humoral antibody responses as a function of disease progression (DP) in a well-defined HIV cohort. We quantified antibodies to HIV-1 gp120, Gag, and CD4 receptor by enzyme-linked immunosorbent assay in sera from a cohort of 97 HIV subjects at defined stages of DP. We also measured antibody-dependent cellular cytotoxicity (ADCC) as a function of the clinical status of the patients. We purified antibodies to CD4 and gp120 and assessed them for specificity, ability to block gp120 binding to target cells, ability to block virus infection, and ability to facilitate ADCC. All of the HIV patient samples were positive for antibodies to HIV gp120 and p24 and 80% showed evidence of hypergammaglobulinemia. Approximately 10% of cohort members were positive for antibodies to CD4, but we noted no significant correlation relevant to DP. There were statistically significant differences between the groups concerning the level of humoral response to gp120 and Gag. However, we observed no distinction in ability of anti-gp120 antibodies purified from each group to neutralize infection. In addition, there was a statistically significant difference in ADCC, with elite controllers exhibiting significantly lower levels of ADCC than the other five groups. We detected IgA anti-gp120 antibodies, but did not correlate their presence with either DP or ADCC levels. The results are consistent with the interpretation that the humoral antibody response to the antigens assessed here represents a signature of the level of viremia but does not correlate with clinical status of HIV infection. [Mh] Termos MeSH primário: Formação de Anticorpos Autoanticorpos/sangue Antígenos CD4/imunologia Progressão da Doença Anticorpos Anti-HIV/sangue Infecções por HIV/imunologia Proteínas do Vírus da Imunodeficiência Humana/imunologia [Mh] Termos MeSH secundário: Autoanticorpos/imunologia Ensaio de Imunoadsorção Enzimática Feminino Anticorpos Anti-HIV/imunologia Infecções por HIV/patologia Seres Humanos Masculino Estudos Prospectivos Fatores de Tempo [Pt] Tipo de publicação: JOURNAL ARTICLE; OBSERVATIONAL STUDY; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S. [Nm] Nome de substância: 0 (Autoantibodies); 0 (CD4 Antigens); 0 (HIV Antibodies); 0 (Human Immunodeficiency Virus Proteins) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180308 [Lr] Data última revisão: 180308 [Sb] Subgrupo de revista: IM; X [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE

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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]: 28701393 [Au] Autor: Madhavi V; Wines BD; Amin J; Emery S; Lopez E; Kelleher A; Center RJ; Hogarth PM; Chung AW; Kent SJ; Stratov I; ENCORE1 Study Group; Sydney LTNP Study Group [Ad] Endereço: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. [Ti] Título: HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV. [So] Source: J Virol;91(18), 2017 Sep 15. [Is] ISSN: 1098-5514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Studying HIV-infected individuals who control HIV replication (elite controllers [ECs]) enables exploration of effective anti-HIV immunity. HIV Env-specific and non-Env-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection, but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects. HIV Env- and Vpu-specific ADCC responses in sera were studied using a novel enzyme-linked immunosorbent assay (ELISA)-based dimeric recombinant soluble FcγRIIIa (rsFcγRIIIa)-binding assay, surface plasmon resonance, antibody-dependent natural killer (NK) cell activation assays, and ADCC-mediated killing assays. ECs had higher levels of HIV Env-specific antibodies capable of binding FcγRIIIa, activating NK cells, and mediating granzyme B activity (all < 0.01) than viremic subjects. ECs also had higher levels of antibodies against a C-terminal 13-mer Vpu peptide capable of mediating FcγRIIIa binding and NK cell activation than viremic subjects (both < 0.05). Our data associate Env-specific and Vpu epitope-specific ADCC in effective immune responses against HIV among ECs. Our findings have implications for understanding the role of ADCC in HIV control. Understanding immune responses associated with elite control of HIV may aid the development of immunotherapeutic and vaccine strategies for controlling HIV infection. Env is a major HIV protein target of functional antibody responses that are heightened in ECs. Interestingly, EC antibodies also target Vpu, an accessory protein crucial to HIV, which degrades CD4 and antagonizes tetherin. Antibodies specific to Vpu are a common feature of the immune response of ECs that may prove to be of functional importance to the design of improved ADCC-based immunotherapy and preventative HIV vaccines. [Mh] Termos MeSH primário: Citotoxicidade Celular Dependente de Anticorpos Anticorpos Anti-HIV/sangue Infecções por HIV/imunologia Proteínas do Vírus da Imunodeficiência Humana/imunologia Proteínas Virais Reguladoras e Acessórias/imunologia Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia [Mh] Termos MeSH secundário: Testes Imunológicos de Citotoxicidade Ensaio de Imunoadsorção Enzimática Sobreviventes de Longo Prazo ao HIV Ressonância de Plasmônio de Superfície [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (HIV Antibodies); 0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (env Gene Products, Human Immunodeficiency Virus); 0 (vpu protein, Human immunodeficiency virus 1) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170714 [St] Status: MEDLINE

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[PMID]: 28604782 [Au] Autor: Blanquart F; Wymant C; Cornelissen M; Gall A; Bakker M; Bezemer D; Hall M; Hillebregt M; Ong SH; Albert J; Bannert N; Fellay J; Fransen K; Gourlay AJ; Grabowski MK; Gunsenheimer-Bartmeyer B; Günthard HF; Kivelä P; Kouyos R; Laeyendecker O; Liitsola K; Meyer L; Porter K; Ristola M; van Sighem A; Vanham G; Berkhout B; Kellam P; Reiss P; Fraser C; BEEHIVE collaboration [Ad] Endereço: Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom. [Ti] Título: Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe. [So] Source: PLoS Biol;15(6):e2001855, 2017 Jun. [Is] ISSN: 1545-7885 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: HIV-1 set-point viral load-the approximately stable value of viraemia in the first years of chronic infection-is a strong predictor of clinical outcome and is highly variable across infected individuals. To better understand HIV-1 pathogenesis and the evolution of the viral population, we must quantify the heritability of set-point viral load, which is the fraction of variation in this phenotype attributable to viral genetic variation. However, current estimates of heritability vary widely, from 6% to 59%. Here we used a dataset of 2,028 seroconverters infected between 1985 and 2013 from 5 European countries (Belgium, Switzerland, France, the Netherlands and the United Kingdom) and estimated the heritability of set-point viral load at 31% (CI 15%-43%). Specifically, heritability was measured using models of character evolution describing how viral load evolves on the phylogeny of whole-genome viral sequences. In contrast to previous studies, (i) we measured viral loads using standardized assays on a sample collected in a strict time window of 6 to 24 months after infection, from which the viral genome was also sequenced; (ii) we compared 2 models of character evolution, the classical "Brownian motion" model and another model ("Ornstein-Uhlenbeck") that includes stabilising selection on viral load; (iii) we controlled for covariates, including age and sex, which may inflate estimates of heritability; and (iv) we developed a goodness of fit test based on the correlation of viral loads in cherries of the phylogenetic tree, showing that both models of character evolution fit the data well. An overall heritability of 31% (CI 15%-43%) is consistent with other studies based on regression of viral load in donor-recipient pairs. Thus, about a third of variation in HIV-1 virulence is attributable to viral genetic variation. [Mh] Termos MeSH primário: Variação Genética Genoma Viral Infecções por HIV/microbiologia Soropositividade para HIV/microbiologia HIV-1/genética Proteínas do Vírus da Imunodeficiência Humana/genética Modelos Genéticos [Mh] Termos MeSH secundário: Adulto Idoso Estudos de Coortes Europa (Continente) Evolução Molecular Feminino Estudo de Associação Genômica Ampla Infecções por HIV/sangue Soropositividade para HIV/sangue HIV-1/crescimento & desenvolvimento HIV-1/isolamento & purificação HIV-1/patogenicidade Proteínas do Vírus da Imunodeficiência Humana/sangue Proteínas do Vírus da Imunodeficiência Humana/metabolismo Seres Humanos Masculino Meia-Idade Filogenia Sistema de Registros Soroconversão Carga Viral Virulência [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Human Immunodeficiency Virus Proteins) [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: 170613 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pbio.2001855

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[PMID]: 28446620 [Au] Autor: Garbelli A; Riva V; Crespan E; Maga G [Ad] Endereço: DNA Enzymology & Molecular Virology Unit, Institute of Molecular Genetics - CNR, via Abbiategrasso 207, Pavia 27100, Italy. [Ti] Título: How to win the HIV-1 drug resistance hurdle race: running faster or jumping higher? [So] Source: Biochem J;474(10):1559-1577, 2017 Apr 26. [Is] ISSN: 1470-8728 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Infections by the human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS), are still totaling an appalling 36.7 millions worldwide, with 1.1 million AIDS deaths/year and a similar number of yearly new infections. All this, in spite of the discovery of HIV-1 as the AIDS etiological agent more than 30 years ago and the introduction of an effective combinatorial antiretroviral therapy (cART), able to control disease progression, more than 20 years ago. Although very effective, current cART is plagued by the emergence of drug-resistant viral variants and most of the efforts in the development of novel direct-acting antiviral agents (DAAs) against HIV-1 have been devoted toward the fighting of resistance. In this review, rather than providing a detailed listing of all the drugs and the corresponding resistance mutations, we aim, through relevant examples, at presenting to the general reader the conceptual shift in the approaches that are being taken to overcome the viral resistance hurdle. From the classic 'running faster' strategy, based on the development of novel DAAs active against the mutant viruses selected by the previous drugs and/or presenting to the virus a high genetic barrier toward the development of resilience, to a 'jumping higher' approach, which looks at the cell, rather than the virus, as a source of valuable drug targets, in order to make the cellular environment non-permissive toward the replication of both wild-type and mutated viruses. [Mh] Termos MeSH primário: Fármacos Anti-HIV/uso terapêutico Desenho de Drogas Farmacorresistência Viral Múltipla Quimioterapia Combinada Infecções por HIV/tratamento farmacológico HIV-1/efeitos dos fármacos Modelos Biológicos [Mh] Termos MeSH secundário: Animais Fármacos Anti-HIV/efeitos adversos Fármacos Anti-HIV/química Fármacos Anti-HIV/farmacologia Terapia Antirretroviral de Alta Atividade/efeitos adversos Antagonistas dos Receptores CCR5/química Antagonistas dos Receptores CCR5/farmacologia Antagonistas dos Receptores CCR5/uso terapêutico RNA Helicases DEAD-box/antagonistas & inibidores RNA Helicases DEAD-box/química RNA Helicases DEAD-box/genética RNA Helicases DEAD-box/metabolismo Quimioterapia Combinada/efeitos adversos Infecções por HIV/metabolismo Infecções por HIV/virologia Inibidores da Protease de HIV/efeitos adversos Inibidores da Protease de HIV/química Inibidores da Protease de HIV/farmacologia Inibidores da Protease de HIV/uso terapêutico HIV-1/genética HIV-1/crescimento & desenvolvimento HIV-1/fisiologia Interações Hospedeiro-Patógeno/efeitos dos fármacos Proteínas do Vírus da Imunodeficiência Humana/antagonistas & inibidores Proteínas do Vírus da Imunodeficiência Humana/química Proteínas do Vírus da Imunodeficiência Humana/genética Proteínas do Vírus da Imunodeficiência Humana/metabolismo Seres Humanos Estrutura Molecular Terapia de Alvo Molecular Mutação Conformação Proteica Inibidores da Transcriptase Reversa/química Inibidores da Transcriptase Reversa/farmacologia Inibidores da Transcriptase Reversa/uso terapêutico Fenômenos Fisiológicos Virais/efeitos dos fármacos Replicação Viral/efeitos dos fármacos [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Anti-HIV Agents); 0 (CCR5 Receptor Antagonists); 0 (HIV Protease Inhibitors); 0 (Human Immunodeficiency Virus Proteins); 0 (Reverse Transcriptase Inhibitors); EC 3.6.1.- (DDX3X protein, human); EC 3.6.4.13 (DEAD-box RNA Helicases) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170623 [Lr] Data última revisão: 170623 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1042/BCJ20160772

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[PMID]: 28358311 [Au] Autor: Pasquereau S; Kumar A; Herbein G [Ad] Endereço: Department of Virology, University of Franche-Comte, University of Bourgogne-Franche-Comté (UBFC), CHRU Besançon, UPRES EA4266 Pathogens & Inflammation/EPILAB, SFR FED 4234, F-25030 Besançon, France. sebastien.pasquereau@univ-fcomte.fr. [Ti] Título: Targeting TNF and TNF Receptor Pathway in HIV-1 Infection: from Immune Activation to Viral Reservoirs. [So] Source: Viruses;9(4), 2017 Mar 30. [Is] ISSN: 1999-4915 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Several cellular functions such as apoptosis, cellular proliferation, inflammation, and immune regulation involve the tumor necrosis factor-α (TNF)/TNF receptor (TNFR) pathway. Human immunodeficiency virus 1 (HIV-1) interacts with the TNF/TNFR pathway. The activation of the TNF/TNFR pathway impacts HIV-1 replication, and the TNF/TNFR pathway is the target of HIV-1 proteins. A hallmark of HIV-1 infection is immune activation and inflammation with increased levels of TNF in the plasma and the tissues. Therefore, the control of the TNF/TNFR pathway by new therapeutic approaches could participate in the control of immune activation and impact both viral replication and viral persistence. In this review, we will describe the intricate interplay between HIV-1 proteins and TNF/TNFR signaling and how TNF/TNFR activation modulates HIV-1 replication and discuss new therapeutic approaches, especially anti-TNF therapy, that could control this pathway and ultimately favor the clearance of infected cells to cure HIV-infected patients. [Mh] Termos MeSH primário: Infecções por HIV/patologia HIV-1/patogenicidade Interações Hospedeiro-Patógeno Proteínas do Vírus da Imunodeficiência Humana/metabolismo Receptores do Fator de Necrose Tumoral/metabolismo Fator de Necrose Tumoral alfa/metabolismo [Mh] Termos MeSH secundário: Infecções por HIV/imunologia HIV-1/imunologia Seres Humanos Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Human Immunodeficiency Virus Proteins); 0 (Receptors, Tumor Necrosis Factor); 0 (TNF protein, human); 0 (Tumor Necrosis Factor-alpha) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170927 [Lr] Data última revisão: 170927 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170331 [St] Status: MEDLINE

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[PMID]: 28346011 [Au] Autor: Soper A; Juarez-Fernandez G; Aso H; Moriwaki M; Yamada E; Nakano Y; Koyanagi Y; Sato K [Ad] Endereço: 1 Laboratory of Systems Virology, Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan. [Ti] Título: Various plus unique: Viral protein U as a plurifunctional protein for HIV-1 replication. [So] Source: Exp Biol Med (Maywood);242(8):850-858, 2017 Apr. [Is] ISSN: 1535-3699 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome, encodes four accessory genes, one of which is viral protein U (Vpu). Recently, the study of Vpu has been of great interest. For instance, various cellular proteins are degraded (e.g. CD4) and down-modulated (e.g. tetherin) by Vpu. Vpu also antagonizes the function of tetherin and inhibits NF-κB. Moreover, Vpu is a viroporin forming ion channels and may represent a promising target for anti-HIV-1 drugs. In this review, we summarize the domains/residues that are responsible for Vpu's functions, describe the current understanding of the role of Vpu in HIV-1-infected cells, and review the effect of Vpu on HIV-1 in replication and pathogenesis. Future investigations that simultaneously assess a combination of Vpu functions are required to clearly delineate the most important functions for viral replication. Impact statement Viral protein U (Vpu) is a unique protein encoded by human immunodeficiency virus type 1 (HIV-1) and related lentiviruses, playing multiple roles in viral replication and pathogenesis. In this review, we briefly summarize the most up-to-date knowledge of HIV-1 Vpu. [Mh] Termos MeSH primário: HIV-1/fisiologia Proteínas do Vírus da Imunodeficiência Humana/fisiologia Proteínas Virais Reguladoras e Acessórias/fisiologia Replicação Viral [Mh] Termos MeSH secundário: Regulação Viral da Expressão Gênica Genoma Viral HIV-1/patogenicidade [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (vpu protein, Human immunodeficiency virus 1) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171001 [Lr] Data última revisão: 171001 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170328 [St] Status: MEDLINE [do] DOI: 10.1177/1535370217697384

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[PMID]: 28331088 [Au] Autor: Richard J; Prévost J; von Bredow B; Ding S; Brassard N; Medjahed H; Coutu M; Melillo B; Bibollet-Ruche F; Hahn BH; Kaufmann DE; Smith AB; Sodroski J; Sauter D; Kirchhoff F; Gee K; Neil SJ; Evans DT; Finzi A [Ad] Endereço: Centre de Recherche du CHUM, Montreal, Quebec, Canada jonathan.richard.1@umontreal.ca andres.finzi@umontreal.ca. [Ti] Título: BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. [So] Source: J Virol;91(11), 2017 Jun 01. [Is] ISSN: 1098-5514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-ß and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-ß and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication. [Mh] Termos MeSH primário: Citotoxicidade Celular Dependente de Anticorpos Antígenos CD/genética Antígenos CD4/imunologia Epitopos/imunologia HIV-1/imunologia Produtos do Gene env do Vírus da Imunodeficiência Humana/genética [Mh] Termos MeSH secundário: Antígenos CD/metabolismo Antígenos CD4/metabolismo Proteínas Ligadas por GPI/deficiência Proteínas Ligadas por GPI/genética Proteínas Ligadas por GPI/metabolismo HIV-1/genética Proteínas do Vírus da Imunodeficiência Humana/genética Proteínas do Vírus da Imunodeficiência Humana/metabolismo Seres Humanos Evasão da Resposta Imune Interferon beta/farmacologia Interleucinas/farmacologia Células Jurkat Mimetismo Molecular Regulação para Cima Proteínas Virais Reguladoras e Acessórias/genética Proteínas Virais Reguladoras e Acessórias/metabolismo Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD); 0 (BST2 protein, human); 0 (CD4 Antigens); 0 (Epitopes); 0 (GPI-Linked Proteins); 0 (Human Immunodeficiency Virus Proteins); 0 (IL27 protein, human); 0 (Interleukins); 0 (Viral Regulatory and Accessory Proteins); 0 (env Gene Products, Human Immunodeficiency Virus); 0 (vpu protein, Human immunodeficiency virus 1); 77238-31-4 (Interferon-beta) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170324 [St] Status: MEDLINE

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[PMID]: 28288652 [Au] Autor: Lukhele S; Cohen ÉA [Ad] Endereço: Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM), 110, Pine Avenue West, Montreal, QC, H2W 1R7, Canada. [Ti] Título: Conserved residues within the HIV-1 Vpu transmembrane-proximal hinge region modulate BST2 binding and antagonism. [So] Source: Retrovirology;14(1):18, 2017 Mar 14. [Is] ISSN: 1742-4690 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: BST2 inhibits HIV-1 release by tethering nascent virions to the surface of infected cells. HIV-1 Vpu overcomes this restriction by removing BST2 from viral budding sites via BST2 intracellular trapping and sequestration, surface downregulation and/or displacement mechanisms. Vpu is composed of a short luminal tail, a transmembrane domain (TMD) and a cytoplasmic hinge region that is followed by two helices. BST2 counteraction relies on the ability of Vpu to physically bind BST2 through TMD interactions and recruit the clathrin-dependent trafficking machinery via a canonical acidic di-leucine signalling motif within the helix-2 of Vpu. The highly conserved Vpu transmembrane-proximal hinge region encompasses residues that resemble an acidic leucine-based trafficking motif, whose functional roles are currently ill-defined. In this study, we investigated the contribution of these residues towards Vpu-mediated BST2 antagonism. RESULTS: We show that while these conserved residues have no intrinsic activity on the cellular distribution of Vpu in the absence of BST2, they regulate the ability of Vpu to bind to BST2 and, consequently, govern both BST2-dependent trafficking properties of the protein as well as its co-localization with BST2. Moreover, these residues, particularly a glutamic acid residue positioned immediately following the TMD, are a determinant not only for efficient targeting of BST2, but also binding and degradation of CD4, another host membrane protein targeted by Vpu. Mechanistically, our data are consistent with a role of these residues in the maintenance of the Vpu TMD conformational configuration such that interactions with membrane-associated host targets are favoured. CONCLUSIONS: Altogether, this work demonstrates an important regulatory role of the transmembrane-proximal Vpu hinge region residues towards enabling the protein to efficiently engage its target host proteins. Thus, this highly conserved, cytosolic Vpu hinge region may represent an attractive target for the development of anti-Vpu inhibitors. [Mh] Termos MeSH primário: Antígenos CD/metabolismo HIV-1/fisiologia Interações Hospedeiro-Patógeno Proteínas do Vírus da Imunodeficiência Humana/genética Proteínas do Vírus da Imunodeficiência Humana/metabolismo Proteínas Virais Reguladoras e Acessórias/genética Proteínas Virais Reguladoras e Acessórias/metabolismo [Mh] Termos MeSH secundário: Análise Mutacional de DNA Proteínas Ligadas por GPI/antagonistas & inibidores Proteínas Ligadas por GPI/metabolismo HIV-1/genética Seres Humanos Ligação Proteica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD); 0 (BST2 protein, human); 0 (GPI-Linked Proteins); 0 (Human Immunodeficiency Virus Proteins); 0 (Viral Regulatory and Accessory Proteins); 0 (vpu 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: 170315 [St] Status: MEDLINE [do] DOI: 10.1186/s12977-017-0345-6

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MEDLINE

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[PMID]: 28225803 [Au] Autor: Deb A; Johnson WA; Kline AP; Scott BJ; Meador LR; Srinivas D; Martin-Garcia JM; Dörner K; Borges CR; Misra R; Hogue BG; Fromme P; Mor TS [Ad] Endereço: School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America. [Ti] Título: Bacterial expression, correct membrane targeting and functional folding of the HIV-1 membrane protein Vpu using a periplasmic signal peptide. [So] Source: PLoS One;12(2):e0172529, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Viral protein U (Vpu) is a type-III integral membrane protein encoded by Human Immunodeficiency Virus-1 (HIV- 1). It is expressed in infected host cells and plays several roles in viral progeny escape from infected cells, including down-regulation of CD4 receptors. But key structure/function questions remain regarding the mechanisms by which the Vpu protein contributes to HIV-1 pathogenesis. Here we describe expression of Vpu in bacteria, its purification and characterization. We report the successful expression of PelB-Vpu in Escherichia coli using the leader peptide pectate lyase B (PelB) from Erwinia carotovora. The protein was detergent extractable and could be isolated in a very pure form. We demonstrate that the PelB signal peptide successfully targets Vpu to the cell membranes and inserts it as a type I membrane protein. PelB-Vpu was biophysically characterized by circular dichroism and dynamic light scattering experiments and was shown to be an excellent candidate for elucidating structural models. [Mh] Termos MeSH primário: Proteínas do Vírus da Imunodeficiência Humana/metabolismo Proteínas Virais Reguladoras e Acessórias/metabolismo [Mh] Termos MeSH secundário: Clonagem Molecular Escherichia coli Expressão Gênica Proteínas do Vírus da Imunodeficiência Humana/genética Seres Humanos Dobramento de Proteína Sinais Direcionadores de Proteínas Proteínas Virais Reguladoras e Acessórias/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Human Immunodeficiency Virus Proteins); 0 (Protein Sorting Signals); 0 (Viral Regulatory and Accessory Proteins); 0 (vpu protein, Human immunodeficiency virus 1) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170223 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0172529

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