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  1 / 3103 MEDLINE  
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[PMID]:28458036
[Au] Autor:Meador LR; Kessans SA; Kilbourne J; Kibler KV; Pantaleo G; Roderiguez ME; Blattman JN; Jacobs BL; Mor TS
[Ad] Endereço:Ira A. Fulton School of Engineering, Arizona State University, Tempe, AZ, USA; Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, AZ, USA.
[Ti] Título:A heterologous prime-boosting strategy with replicating Vaccinia virus vectors and plant-produced HIV-1 Gag/dgp41 virus-like particles.
[So] Source:Virology;507:242-256, 2017 07.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Showing modest efficacy, the RV144 HIV-1 vaccine clinical trial utilized a non-replicating canarypox viral vector and a soluble gp120 protein boost. Here we built upon the RV144 strategy by developing a novel combination of a replicating, but highly-attenuated Vaccinia virus vector, NYVAC-KC, and plant-produced HIV-1 virus-like particles (VLPs). Both components contained the full-length Gag and a membrane anchored truncated gp41 presenting the membrane proximal external region with its conserved broadly neutralizing epitopes in the pre-fusion conformation. We tested different prime/boost combinations of these components in mice and showed that the group primed with NYVAC-KC and boosted with both the viral vectors and plant-produced VLPs have the most robust Gag-specific CD8 T cell responses, at 12.7% of CD8 T cells expressing IFN-γ in response to stimulation with five Gag epitopes. The same immunization group elicited the best systemic and mucosal antibody responses to Gag and dgp41 with a bias towards IgG1.
[Mh] Termos MeSH primário: Vacinas contra a AIDS/administração & dosagem
Proteína gp41 do Envelope de HIV/imunologia
Infecções por HIV/imunologia
HIV-1/imunologia
Imunização/métodos
Tabaco/metabolismo
Vírus Vaccinia/fisiologia
Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
[Mh] Termos MeSH secundário: Vacinas contra a AIDS/imunologia
Animais
Anticorpos Neutralizantes/imunologia
Formação de Anticorpos
Feminino
Vetores Genéticos/genética
Vetores Genéticos/fisiologia
Anticorpos Anti-HIV/imunologia
Proteína gp41 do Envelope de HIV/administração & dosagem
Proteína gp41 do Envelope de HIV/genética
Infecções por HIV/prevenção & controle
Infecções por HIV/virologia
HIV-1/genética
Seres Humanos
Imunização Secundária
Camundongos
Camundongos Endogâmicos C57BL
Tabaco/genética
Tabaco/virologia
Vacinas de Partículas Semelhantes a Vírus/genética
Vacinas de Partículas Semelhantes a Vírus/imunologia
Vírus Vaccinia/genética
Replicação Viral
Produtos do Gene gag do Vírus da Imunodeficiência Humana/administração & dosagem
Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (AIDS Vaccines); 0 (Antibodies, Neutralizing); 0 (HIV Antibodies); 0 (HIV Envelope Protein gp41); 0 (Vaccines, Virus-Like Particle); 0 (gag Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


  2 / 3103 MEDLINE  
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[PMID]:28994411
[Au] Autor:Gristick HB; Wang H; Bjorkman PJ
[Ad] Endereço:Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
[Ti] Título:X-ray and EM structures of a natively glycosylated HIV-1 envelope trimer.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 10):822-828, 2017 Oct 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The structural and biochemical characterization of broadly neutralizing anti-HIV-1 antibodies (bNAbs) has been essential in guiding the design of potential vaccines to prevent infection by HIV-1. While these studies have revealed critical mechanisms by which bNAbs recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env), they have been limited to the visualization of high-mannose glycan forms only, since heterogeneity introduced from the presence of complex glycans makes it difficult to obtain high-resolution structures. 3.5 and 3.9 Šresolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation were solved, revealing a glycan shield of high-mannose and complex-type N-glycans that were used to define the complete epitopes of two bNAbs. Here, the refinement of the N-glycans in the crystal structures is discussed and comparisons are made with glycan densities in glycosylated Env structures derived by single-particle cryo-electron microscopy.
[Mh] Termos MeSH primário: HIV-1/química
Manose/análise
Polissacarídeos/análise
Produtos do Gene env do Vírus da Imunodeficiência Humana/química
[Mh] Termos MeSH secundário: Anticorpos Neutralizantes/química
Microscopia Crioeletrônica
Cristalografia por Raios X
Glicosilação
Anticorpos Anti-HIV/química
Proteína gp120 do Envelope de HIV/química
Proteína gp120 do Envelope de HIV/ultraestrutura
Proteína gp41 do Envelope de HIV/química
Proteína gp41 do Envelope de HIV/ultraestrutura
Infecções por HIV/virologia
HIV-1/ultraestrutura
Seres Humanos
Modelos Moleculares
Conformação Proteica
Multimerização Proteica
Produtos do Gene env do Vírus da Imunodeficiência Humana/ultraestrutura
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (HIV Antibodies); 0 (HIV Envelope Protein gp120); 0 (HIV Envelope Protein gp41); 0 (Polysaccharides); 0 (env Gene Products, Human Immunodeficiency Virus); PHA4727WTP (Mannose)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317013353


  3 / 3103 MEDLINE  
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[PMID]:28930470
[Au] Autor:Serrano S; Huarte N; Rujas E; Andreu D; Nieva JL; Jiménez MA
[Ad] Endereço:Institute of Physical Chemistry "Rocasolano" (IQFR-CSIC) , Serrano 119, E-28006 Madrid, Spain.
[Ti] Título:Structure-Related Roles for the Conservation of the HIV-1 Fusion Peptide Sequence Revealed by Nuclear Magnetic Resonance.
[So] Source:Biochemistry;56(41):5503-5511, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite extensive characterization of the human immunodeficiency virus type 1 (HIV-1) hydrophobic fusion peptide (FP), the structure-function relationships underlying its extraordinary degree of conservation remain poorly understood. Specifically, the fact that the tandem repeat of the FLGFLG tripeptide is absolutely conserved suggests that high hydrophobicity may not suffice to unleash FP function. Here, we have compared the nuclear magnetic resonance (NMR) structures adopted in nonpolar media by two FP surrogates, wtFP-tag and scrFP-tag, which had equal hydrophobicity but contained wild-type and scrambled core sequences LFLGFLG and FGLLGFL, respectively. In addition, these peptides were tagged at their C-termini with an epitope sequence that folded independently, thereby allowing Western blot detection without interfering with FP structure. We observed similar α-helical FP conformations for both specimens dissolved in the low-polarity medium 25% (v/v) 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), but important differences in contact with micelles of the membrane mimetic dodecylphosphocholine (DPC). Thus, whereas wtFP-tag preserved a helix displaying a Gly-rich ridge, the scrambled sequence lost in great part the helical structure upon being solubilized in DPC. Western blot analyses further revealed the capacity of wtFP-tag to assemble trimers in membranes, whereas membrane oligomers were not observed in the case of the scrFP-tag sequence. We conclude that, beyond hydrophobicity, preserving sequence order is an important feature for defining the secondary structures and oligomeric states adopted by the HIV FP in membranes.
[Mh] Termos MeSH primário: Proteína gp41 do Envelope de HIV/metabolismo
Modelos Moleculares
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sequência Conservada
Cristalografia por Raios X
Bases de Dados de Proteínas
Epitopos
Proteína gp41 do Envelope de HIV/química
Proteína gp41 do Envelope de HIV/genética
Interações Hidrofóbicas e Hidrofílicas
Micelas
Ressonância Magnética Nuclear Biomolecular
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Fosforilcolina/análogos & derivados
Fosforilcolina/química
Fosforilcolina/metabolismo
Conformação Proteica
Conformação Proteica em alfa-Hélice
Multimerização Proteica
Estrutura Secundária de Proteína
Estrutura Terciária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Técnicas de Síntese em Fase Sólida
Sequências de Repetição em Tandem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epitopes); 0 (HIV Envelope Protein gp41); 0 (Micelles); 0 (Peptide Fragments); 0 (Recombinant Proteins); 0 (gp41 protein, Human immunodeficiency virus 1); 107-73-3 (Phosphorylcholine); 53949-18-1 (dodecylphosphocholine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00745


  4 / 3103 MEDLINE  
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[PMID]:28825711
[Au] Autor:Pancera M; Lai YT; Bylund T; Druz A; Narpala S; O'Dell S; Schön A; Bailer RT; Chuang GY; Geng H; Louder MK; Rawi R; Soumana DI; Finzi A; Herschhorn A; Madani N; Sodroski J; Freire E; Langley DR; Mascola JR; McDermott AB; Kwong PD
[Ad] Endereço:Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
[Ti] Título:Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529.
[So] Source:Nat Chem Biol;13(10):1115-1122, 2017 Oct.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the ß20-21 hairpin. In both structures, the ß20-21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.
[Mh] Termos MeSH primário: Proteína gp120 do Envelope de HIV/química
Proteína gp41 do Envelope de HIV/química
Piperazinas/química
Bibliotecas de Moléculas Pequenas/química
Triazóis/química
Internalização do Vírus/efeitos dos fármacos
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Proteína gp120 do Envelope de HIV/antagonistas & inibidores
Proteína gp41 do Envelope de HIV/antagonistas & inibidores
Modelos Moleculares
Piperazinas/farmacologia
Bibliotecas de Moléculas Pequenas/farmacologia
Relação Estrutura-Atividade
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BMS-378806); 0 (BMS-626529); 0 (HIV Envelope Protein gp120); 0 (HIV Envelope Protein gp41); 0 (Piperazines); 0 (Small Molecule Libraries); 0 (Triazoles)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2460


  5 / 3103 MEDLINE  
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[PMID]:28794027
[Au] Autor:Han Q; Williams WB; Saunders KO; Seaton KE; Wiehe KJ; Vandergrift N; Von Holle TA; Trama AM; Parks RJ; Luo K; Gurley TC; Kepler TB; Marshall DJ; Montefiori DC; Sutherland LL; Alam MS; Whitesides JF; Bowman CM; Permar SR; Graham BS; Mascola JR; Seed PC; Van Rompay KKA; Tomaras GD; Moody MA; Haynes BF
[Ad] Endereço:Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
[Ti] Título:HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques.
[So] Source:J Virol;91(21), 2017 Nov 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dominant antibody responses in vaccinees who received the HIV-1 multiclade (A, B, and C) envelope (Env) DNA/recombinant adenovirus virus type 5 (rAd5) vaccine studied in HIV-1 Vaccine Trials Network (HVTN) efficacy trial 505 (HVTN 505) targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs), which are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization. We found that the DNA/rAd5 vaccine elicited a higher frequency of gp41-reactive memory B cells than gp120-memory B cells in adult and neonatal RMs. Analysis of the vaccine-induced Env-reactive B cell repertoire revealed that the majority of HIV-1 Env-reactive antibodies in both adult and neonatal RMs were targeted to gp41. Interestingly, a subset of gp41-reactive antibodies isolated from RMs cross-reacted with host antigens, including autologous intestinal microbiota. Thus, gp41-containing DNA/rAd5 vaccine induced dominant gp41-microbiota cross-reactive antibodies derived from blood memory B cells in RMs as observed in the HVTN 505 vaccine efficacy trial. These data demonstrated that RMs can be used to investigate gp41 immunodominance in candidate HIV-1 vaccines. Moreover, colonization of neonatal RMs occurred within the first week of life, and immunization of neonatal RMs during this time also induced a dominant gp41-reactive antibody response. Our results are critical to current work in the HIV-1 vaccine field evaluating the phenomenon of gp41 immunodominance induced by HIV-1 Env gp140 in RMs and humans. Our data demonstrate that RMs are an appropriate animal model to study this phenomenon and to determine the immunogenicity in new HIV-1 Env trimer vaccine designs. The demonstration of gp41 immunodominance in memory B cells of both adult and neonatal RMs indicated that early vaccination could not overcome gp41 dominant responses.
[Mh] Termos MeSH primário: Vacinas contra a AIDS/administração & dosagem
Adenoviridae/genética
DNA Viral/genética
Anticorpos Anti-HIV/imunologia
Proteína gp41 do Envelope de HIV/imunologia
Infecções por HIV/imunologia
HIV-1/imunologia
[Mh] Termos MeSH secundário: Adenoviridae/imunologia
Animais
Animais Recém-Nascidos
Formação de Anticorpos/imunologia
Sequência de Bases
Reações Cruzadas/imunologia
DNA Viral/imunologia
Feminino
Infecções por HIV/prevenção & controle
Infecções por HIV/virologia
Seres Humanos
Macaca mulatta
Vacinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AIDS Vaccines); 0 (DNA, Viral); 0 (HIV Antibodies); 0 (HIV Envelope Protein gp41)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE


  6 / 3103 MEDLINE  
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[PMID]:28711731
[Au] Autor:Deng L; Xue X; Shen C; Song X; Wang C; Wang N
[Ad] Endereço:Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
[Ti] Título:Insulin chains as efficient fusion tags for prokaryotic expression of short peptides.
[So] Source:Protein Expr Purif;138:46-55, 2017 Oct.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Insulin chains are usually expressed in Escherichia coli as fusion proteins with different tags, including various low molecular weight peptide tags. The objective of this study was to determine if insulin chains could facilitate the recombinant expression of other target proteins, with an emphasis on low molecular weight peptides. A series of short peptides were fused to mini-proinsulin, chain B or chain A, and induced for expression in Escherichia coli. All the tested peptides including glucagon-like peptide 1 (GLP-1), a C-terminal extended GLP-1, oxyntomodulin, enfuvirtide, linaclotide, and an unstructured artificial peptide were expressed with reasonable yields, identified by Tricine-SDS-PAGE and immunoblotting. All recombinant products were expressed in inclusion bodies. The effective accumulation of products was largely attributed to the insoluble expression induced by fusion with insulin chains, and was confirmed by the fusion expression of transthyretin. Insulin chains thus show promise as efficient fusion tags for mass production of heterologous peptides in prokaryotes.
[Mh] Termos MeSH primário: Vetores Genéticos/metabolismo
Peptídeo 1 Semelhante ao Glucagon/genética
Proteína gp41 do Envelope de HIV/genética
Fragmentos de Peptídeos/genética
Peptídeos/genética
Proinsulina/genética
Proteínas Recombinantes de Fusão/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Western Blotting
Clonagem Molecular
Eletroforese em Gel de Poliacrilamida
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Vetores Genéticos/química
Peptídeo 1 Semelhante ao Glucagon/isolamento & purificação
Peptídeo 1 Semelhante ao Glucagon/metabolismo
Proteína gp41 do Envelope de HIV/isolamento & purificação
Proteína gp41 do Envelope de HIV/metabolismo
Seres Humanos
Corpos de Inclusão/química
Peso Molecular
Fragmentos de Peptídeos/isolamento & purificação
Fragmentos de Peptídeos/metabolismo
Peptídeos/isolamento & purificação
Peptídeos/metabolismo
Pré-Albumina/genética
Pré-Albumina/isolamento & purificação
Pré-Albumina/metabolismo
Proinsulina/isolamento & purificação
Proinsulina/metabolismo
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/metabolismo
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Envelope Protein gp41); 0 (Peptide Fragments); 0 (Peptides); 0 (Prealbumin); 0 (Recombinant Fusion Proteins); 127279-05-4 (miniproinsulin); 19OWO1T3ZE (enfuvirtide); 89750-14-1 (Glucagon-Like Peptide 1); 9035-68-1 (Proinsulin); N0TXR0XR5X (linaclotide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


  7 / 3103 MEDLINE  
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[PMID]:28671952
[Au] Autor:Nabi R; Moldoveanu Z; Wei Q; Golub ET; Durkin HG; Greenblatt RM; Herold BC; Nowicki MJ; Kassaye S; Cho MW; Pinter A; Landay AL; Mestecky J; Kozlowski PA
[Ad] Endereço:Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
[Ti] Título:Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy.
[So] Source:PLoS One;12(7):e0180245, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication.
[Mh] Termos MeSH primário: Terapia Antirretroviral de Alta Atividade
Proteína gp41 do Envelope de HIV/imunologia
Infecções por HIV/imunologia
Imunoglobulina A/sangue
[Mh] Termos MeSH secundário: Adulto
Afinidade de Anticorpos
Ensaio de Imunoadsorção Enzimática
Feminino
Anticorpos Anti-HIV/biossíntese
Infecções por HIV/tratamento farmacológico
Seres Humanos
Imunoglobulina G/sangue
Masculino
Meia-Idade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Antibodies); 0 (HIV Envelope Protein gp41); 0 (Immunoglobulin A); 0 (Immunoglobulin G)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180245


  8 / 3103 MEDLINE  
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[PMID]:28659478
[Au] Autor:Ding X; Zhang X; Chong H; Zhu Y; Wei H; Wu X; He J; Wang X; He Y
[Ad] Endereço:MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China.
[Ti] Título:Enfuvirtide (T20)-Based Lipopeptide Is a Potent HIV-1 Cell Fusion Inhibitor: Implications for Viral Entry and Inhibition.
[So] Source:J Virol;91(18), 2017 Sep 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The peptide drug enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy for HIV-1 infection, but it has relatively low antiviral activity and easily induces drug resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors, such as LP-11 and LP-19, which mainly target the gp41 pocket site, have greatly improved antiviral potency and stability. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site. First, the C-terminal tryptophan-rich motif (TRM) of T20 was verified to be essential for its target binding and inhibition; then, a novel lipopeptide, termed LP-40, was created by replacing the TRM with a fatty acid group. LP-40 showed markedly enhanced binding affinity for the target site and dramatically increased inhibitory activity on HIV-1 membrane fusion, entry, and infection. Unlike LP-11 and LP-19, which required a flexible linker between the peptide sequence and the lipid moiety, addition of a linker to LP-40 sharply reduced its potency, implying different binding modes with the extended N-terminal helices of gp41. Also, interestingly, LP-40 showed more potent activity than LP-11 in inhibiting HIV-1 Env-mediated cell-cell fusion while it was less active than LP-11 in inhibiting pseudovirus entry, and the two inhibitors displayed synergistic antiviral effects. The crystal structure of LP-40 in complex with a target peptide revealed their key binding residues and motifs. Combined, our studies have not only provided a potent HIV-1 fusion inhibitor, but also revealed new insights into the mechanisms of viral inhibition. T20 is the only membrane fusion inhibitor available for treatment of viral infection; however, T20 requires high doses and has a low genetic barrier for resistance, and its inhibitory mechanism and structural basis remain unclear. Here, we report the design of LP-40, a T20-based lipopeptide inhibitor that has greatly improved anti-HIV activity and is a more potent inhibitor of cell-cell fusion than of cell-free virus infection. The binding modes of two classes of membrane-anchoring lipopeptides (LP-40 and LP-11) verify the current fusion model in which an extended prehairpin structure bridges the viral and cellular membranes, and their complementary effects suggest a vital strategy for combination therapy of HIV-1 infection. Moreover, our understanding of the mechanism of action of T20 and its derivatives benefits from the crystal structure of LP-40.
[Mh] Termos MeSH primário: Proteína gp41 do Envelope de HIV/farmacologia
Inibidores da Fusão de HIV/farmacologia
HIV/efeitos dos fármacos
Lipopeptídeos/farmacologia
Fragmentos de Peptídeos/farmacologia
Internalização do Vírus/efeitos dos fármacos
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Inibidores da Fusão de HIV/química
Inibidores da Fusão de HIV/isolamento & purificação
Lipopeptídeos/química
Lipopeptídeos/isolamento & purificação
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Envelope Protein gp41); 0 (HIV Fusion Inhibitors); 0 (Lipopeptides); 0 (Peptide Fragments); 19OWO1T3ZE (enfuvirtide)
[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:170630
[St] Status:MEDLINE


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[PMID]:28558972
[Au] Autor:McGee TD; Yi HA; Allen WJ; Jacobs A; Rizzo RC
[Ad] Endereço:Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States.
[Ti] Título:Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer.
[So] Source:Bioorg Med Chem Lett;27(14):3177-3184, 2017 07 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N-heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. (Bioorg. Med. Chem Lett.2015, 25 2853-59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC =37.81µM), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic.
[Mh] Termos MeSH primário: Desenho de Drogas
Proteína gp41 do Envelope de HIV/antagonistas & inibidores
Inibidores da Fusão de HIV/química
HIV/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Proteína gp41 do Envelope de HIV/metabolismo
Inibidores da Fusão de HIV/metabolismo
Inibidores da Fusão de HIV/toxicidade
Seres Humanos
Simulação de Acoplamento Molecular
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/metabolismo
Estrutura Terciária de Proteína
Internalização do Vírus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (HIV Envelope Protein gp41); 0 (HIV Fusion Inhibitors); 0 (Peptide Fragments); 0 (peptide C34)
[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:170601
[St] Status:MEDLINE


  10 / 3103 MEDLINE  
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[PMID]:28514686
[Au] Autor:Guenaga J; Garces F; de Val N; Stanfield RL; Dubrovskaya V; Higgins B; Carrette B; Ward AB; Wilson IA; Wyatt RT
[Ad] Endereço:IAVI Neutralizing Antibody Center at The Scripps Research Institute, La Jolla, CA 92037, USA.
[Ti] Título:Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein.
[So] Source:Immunity;46(5):792-803.e3, 2017 May 16.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state. We generated a stabilized, soluble clade C Env (16055 NFL) and determined its crystal structure at 3.9 Å. Its overall conformation is similar to SOSIP.664 and native Env trimers but includes a covalent linker between gp120 and gp41, an engineered 201-433 disulfide bond, and density corresponding to 22 N-glycans. Env-structure-guided design strategies resulted in multiple homogeneous cross-clade immunogens with the potential to advance HIV vaccine development.
[Mh] Termos MeSH primário: Substituição de Aminoácidos
Glicina/química
HIV-1/imunologia
Conformação Proteica em alfa-Hélice
Produtos do Gene env do Vírus da Imunodeficiência Humana/química
Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
[Mh] Termos MeSH secundário: Anticorpos Neutralizantes/química
Anticorpos Neutralizantes/imunologia
Anticorpos Neutralizantes/metabolismo
Sítios de Ligação
Genótipo
Glicina/genética
Glicosilação
Anticorpos Anti-HIV/química
Anticorpos Anti-HIV/imunologia
Anticorpos Anti-HIV/metabolismo
Proteína gp120 do Envelope de HIV/química
Proteína gp120 do Envelope de HIV/genética
Proteína gp120 do Envelope de HIV/imunologia
Proteína gp41 do Envelope de HIV/química
Proteína gp41 do Envelope de HIV/genética
Proteína gp41 do Envelope de HIV/imunologia
HIV-1/classificação
HIV-1/genética
Seres Humanos
Modelos Moleculares
Mutação
Ligação Proteica/imunologia
Engenharia de Proteínas
Multimerização Proteica
Estabilidade Proteica
Proteólise
Solubilidade
Relação Estrutura-Atividade
Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (HIV Antibodies); 0 (HIV Envelope Protein gp120); 0 (HIV Envelope Protein gp41); 0 (env Gene Products, Human Immunodeficiency Virus); TE7660XO1C (Glycine)
[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:170518
[St] Status:MEDLINE



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