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[PMID]:29364927
[Au] Autor:Ferdin J; Goricar K; Dolzan V; Plemenitas A; Martin JN; Peterlin BM; Deeks SG; Lenassi M
[Ad] Endereço:Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
[Ti] Título:Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA.
[So] Source:PLoS One;13(1):e0191613, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To address the role of translationally active HIV reservoir in chronic inflammation and non-AIDS related disorders, we first need a simple and accurate assay to evaluate viral protein expression in virally suppressed subjects. DESIGN: We optimized an HIV Nef enzyme-linked immunosorbent assay (ELISA) and used it to quantify plasma Nef levels as an indicator of the leaky HIV reservoir in an HIV-infected cohort. METHODS: This study accessed 134 plasma samples from a well-characterized cohort study of HIV-infected and uninfected adults in San Francisco (the SCOPE cohort). We optimized an ELISA for detection of plasma Nef in HIV-negative subjects and HIV-infected non-controllers, and evaluated its utility to quantify plasma Nef levels in a cross-sectional study of ART-suppressed and elite controller HIV-infected subjects. RESULTS: Here, we describe the performance of an optimized HIV Nef ELISA. When we applied this assay to the study cohort we found that plasma Nef levels were correlated with plasma HIV RNA levels in untreated disease. However, we were able to detect Nef in plasma of approximately half of subjects on ART or with elite control, despite the lack of detectable plasma HIV RNA levels using standard assays. Plasma Nef levels were not consistently associated with CD4+ T-cell count, CD8+ T-cell count, self-reported nadir CD4+ T-cell count or the CD4+/CD8+ T-cell ratio in HIV-infected subjects. CONCLUSION: Since plasma HIV RNA levels are undetectable in virally suppressed subjects, it is reasonable to assume that viral protein expression in leaky reservoir, and not plasma virions, is the source of Nef accumulating in plasma. To examine this further, improvements of the assay sensitivity, by lowering the background through improvements in the quality of Nef antibodies, and detailed characterization of the HIV reservoirs are needed.
[Mh] Termos MeSH primário: Produtos do Gene nef/sangue
Infecções por HIV/sangue
RNA Viral/sangue
Carga Viral
[Mh] Termos MeSH secundário: Adulto
Idoso
Ensaio de Imunoadsorção Enzimática
Feminino
Seres Humanos
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Gene Products, nef); 0 (RNA, Viral)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191613


  2 / 1280 MEDLINE  
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[PMID]:28333940
[Au] Autor:Lu W; Wan Y; Ma F; Johnson RP; Li Q
[Ad] Endereço:School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
[Ti] Título:Distinct transcriptome profiles of Gag-specific CD8+ T cells temporally correlated with the protection elicited by SIVΔnef live attenuated vaccine.
[So] Source:PLoS One;12(3):e0173929, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The live attenuated vaccine (LAV) SIVmac239Δnef (SIVΔnef) confers the best protection among all the vaccine modalities tested in rhesus macaque model of HIV-1 infection. This vaccine has a unique feature of time-dependent protection: macaques are not protected at 3-5 weeks post vaccination (WPV), whereas immune protection emerges between 15 and 20 WPV. Although the exact mechanisms of the time-dependent protection remain incompletely understood, studies suggested that both cellular and humoral immunities contribute to this time-dependent protection. To further elucidate the mechanisms of protection induced by SIVΔnef, we longitudinally compared the global gene expression profiles of SIV Gag-CM9+ CD8+ (Gag-specific CD8+) T cells from peripheral blood of Mamu-A*01+ rhesus macaques at 3 and 20 WPV using rhesus microarray. We found that gene expression profiles of Gag-specific CD8+ T cells at 20 WPV are qualitatively different from those at 3 WPV. At 20 WPV, the most significant transcriptional changes of Gag-specific CD8+ T cells were genes involved in TCR signaling, differentiation and maturation toward central memory cells, with increased expression of CCR7, TCRα, TCRß, CD28 and decreased expression of CTLA-4, IFN-γ, RANTES, granzyme A and B. Our study suggests that a higher quality of SIV-specific CD8+ T cells elicited by SIVΔnef over time contributes to the maturation of time-dependent protection.
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/metabolismo
Produtos do Gene gag/imunologia
Vacinas contra a SAIDS/imunologia
Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle
Vírus da Imunodeficiência Símia/imunologia
Transcriptoma
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD8-Positivos/imunologia
Produtos do Gene nef/imunologia
Imunidade Celular
Imunidade Humoral
Macaca mulatta/imunologia
Macaca mulatta/virologia
Masculino
Síndrome de Imunodeficiência Adquirida dos Símios/imunologia
Fatores de Tempo
Vacinas Atenuadas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gene Products, gag); 0 (Gene Products, nef); 0 (SAIDS Vaccines); 0 (Vaccines, Attenuated)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173929


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[PMID]:27894306
[Au] Autor:Choi E; Michalski CJ; Choo SH; Kim GN; Banasikowska E; Lee S; Wu K; An HY; Mills A; Schneider S; Bredeek UF; Coulston DR; Ding S; Finzi A; Tian M; Klein K; Arts EJ; Mann JF; Gao Y; Kang CY
[Ad] Endereço:Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1400 Western Road, London, ON, N6G 2V4, Canada.
[Ti] Título:First Phase I human clinical trial of a killed whole-HIV-1 vaccine: demonstration of its safety and enhancement of anti-HIV antibody responses.
[So] Source:Retrovirology;13(1):82, 2016 Nov 28.
[Is] ISSN:1742-4690
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Vaccination with inactivated (killed) whole-virus particles has been used to prevent a wide range of viral diseases. However, for an HIV vaccine this approach has been largely negated due to inherent safety concerns, despite the ability of killed whole-virus vaccines to generate a strong, predominantly antibody-mediated immune response in vivo. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence for the Env signal peptide with that of honeybee melittin signal peptide to produce a less virulent and more replication efficient virus. This genetically modified virus (gmHIV-1 ) was inactivated and formulated as a killed whole-HIV vaccine, and then used for a Phase I human clinical trial (Trial Registration: Clinical Trials NCT01546818). The gmHIV-1 was propagated in the A3.01 human T cell line followed by virus purification and inactivation with aldrithiol-2 and γ-irradiation. Thirty-three HIV-1 positive volunteers receiving cART were recruited for this observer-blinded, placebo-controlled Phase I human clinical trial to assess the safety and immunogenicity. RESULTS: Genetically modified and killed whole-HIV-1 vaccine, SAV001, was well tolerated with no serious adverse events. HIV-1 -specific PCR showed neither evidence of vaccine virus replication in the vaccine virus-infected human T lymphocytes in vitro nor in the participating volunteers receiving SAV001 vaccine. Furthermore, SAV001 with adjuvant significantly increased the pre-existing antibody response to HIV-1 proteins. Antibodies in the plasma of vaccinees were also found to recognize HIV-1 envelope protein on the surface of infected cells as well as showing an enhancement of broadly neutralizing antibodies inhibiting tier I and II of HIV-1 B, D, and A subtypes. CONCLUSION: The killed whole-HIV vaccine, SAV001, is safe and triggers anti-HIV immune responses. It remains to be determined through an appropriate trial whether this immune response prevents HIV infection.
[Mh] Termos MeSH primário: Vacinas contra a AIDS
Anticorpos Neutralizantes/sangue
Anticorpos Anti-HIV/sangue
Infecções por HIV/prevenção & controle
HIV-1/imunologia
Imunogenicidade da Vacina
[Mh] Termos MeSH secundário: Vacinas contra a AIDS/administração & dosagem
Vacinas contra a AIDS/efeitos adversos
Vacinas contra a AIDS/imunologia
Adulto
Animais
Anticorpos Neutralizantes/imunologia
Abelhas/genética
Feminino
Produtos do Gene nef/genética
Anticorpos Anti-HIV/imunologia
Infecções por HIV/imunologia
HIV-1/genética
Proteínas do Vírus da Imunodeficiência Humana/genética
Seres Humanos
Masculino
Meia-Idade
Sinais Direcionadores de Proteínas
Vacinas de Produtos Inativados/administração & dosagem
Vacinas de Produtos Inativados/efeitos adversos
Vacinas de Produtos Inativados/imunologia
Proteínas Virais Reguladoras e Acessórias/genética
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (AIDS Vaccines); 0 (Antibodies, Neutralizing); 0 (Gene Products, nef); 0 (HIV Antibodies); 0 (Human Immunodeficiency Virus Proteins); 0 (Protein Sorting Signals); 0 (Vaccines, Inactivated); 0 (Viral Regulatory and Accessory Proteins); 0 (vpu protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161130
[St] Status:MEDLINE


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[PMID]:27481843
[Au] Autor:Paquin-Proulx D; Gibbs A; Bächle SM; Checa A; Introini A; Leeansyah E; Wheelock CE; Nixon DF; Broliden K; Tjernlund A; Moll M; Sandberg JK
[Ad] Endereço:Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
[Ti] Título:Innate Invariant NKT Cell Recognition of HIV-1-Infected Dendritic Cells Is an Early Detection Mechanism Targeted by Viral Immune Evasion.
[So] Source:J Immunol;197(5):1843-51, 2016 Sep 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Invariant NKT (iNKT) cells are innate-like T cells that respond rapidly with a broad range of effector functions upon recognition of glycolipid Ags presented by CD1d. HIV-1 carries Nef- and Vpu-dependent mechanisms to interfere with CD1d surface expression, indirectly suggesting a role for iNKT cells in control of HIV-1 infection. In this study, we investigated whether iNKT cells can participate in the innate cell-mediated immune response to HIV-1. Infection of dendritic cells (DCs) with Nef- and Vpu-deficient HIV-1 induced upregulation of CD1d in a TLR7-dependent manner. Infection of DCs caused modulation of enzymes in the sphingolipid pathway and enhanced expression of the endogenous glucosylceramide Ag. Importantly, iNKT cells responded specifically to rare DCs productively infected with Nef- and Vpu-defective HIV-1. Transmitted founder viral isolates differed in their CD1d downregulation capacity, suggesting that diverse strains may be differentially successful in inhibiting this pathway. Furthermore, both iNKT cells and DCs expressing CD1d and HIV receptors resided in the female genital mucosa, a site where HIV-1 transmission occurs. Taken together, these findings suggest that innate iNKT cell sensing of HIV-1 infection in DCs is an early immune detection mechanism, which is independent of priming and adaptive recognition of viral Ag, and is actively targeted by Nef- and Vpu-dependent viral immune evasion mechanisms.
[Mh] Termos MeSH primário: Apresentação do Antígeno
Células Dendríticas/imunologia
HIV-1/imunologia
Evasão da Resposta Imune
Células T Matadoras Naturais/imunologia
[Mh] Termos MeSH secundário: Antígenos CD1d/genética
Antígenos CD1d/imunologia
Células Dendríticas/virologia
Feminino
Produtos do Gene nef/deficiência
Produtos do Gene nef/genética
Produtos do Gene nef/metabolismo
Glucosilceramidas/genética
Glucosilceramidas/imunologia
Células HEK293
Antígenos HIV/imunologia
Infecções por HIV/imunologia
Infecções por HIV/virologia
HIV-1/genética
Proteínas do Vírus da Imunodeficiência Humana/deficiência
Proteínas do Vírus da Imunodeficiência Humana/genética
Proteínas do Vírus da Imunodeficiência Humana/metabolismo
Seres Humanos
Imunidade Celular
Células Matadoras Naturais/imunologia
Ativação Linfocitária
Receptor 7 Toll-Like/genética
Receptor 7 Toll-Like/imunologia
Proteínas Virais Reguladoras e Acessórias/deficiência
Proteínas Virais Reguladoras e Acessórias/genética
Proteínas Virais Reguladoras e Acessórias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD1d); 0 (CD1D protein, human); 0 (Gene Products, nef); 0 (Glucosylceramides); 0 (HIV Antigens); 0 (Human Immunodeficiency Virus Proteins); 0 (TLR7 protein, human); 0 (Toll-Like Receptor 7); 0 (Viral Regulatory and Accessory Proteins); 0 (vpu protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170824
[Lr] Data última revisão:
170824
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160803
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600556


  5 / 1280 MEDLINE  
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[PMID]:27399760
[Au] Autor:Sabino Cunha M; Lima Sampaio T; Peterlin BM; Jesus da Costa L
[Ad] Endereço:Departamento de Virologia-Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho 373-CCS-Bloco I, Rio de Janeiro 21941-902, Brazil. marcela.scw@gmail.com.
[Ti] Título:A Truncated Nef Peptide from SIVcpz Inhibits the Production of HIV-1 Infectious Progeny.
[So] Source:Viruses;8(7), 2016 Jul 07.
[Is] ISSN:1999-4915
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Nef proteins from all primate Lentiviruses, including the simian immunodeficiency virus of chimpanzees (SIVcpz), increase viral progeny infectivity. However, the function of Nef involved with the increase in viral infectivity is still not completely understood. Nonetheless, until now, studies investigating the functions of Nef from SIVcpz have been conducted in the context of the HIV-1 proviruses. In an attempt to investigate the role played by Nef during the replication cycle of an SIVcpz, a Nef-defective derivative was obtained from the SIVcpzWTGab2 clone by introducing a frame shift mutation at a unique restriction site within the nef sequence. This nef-deleted clone expresses an N-terminal 74-amino acid truncated peptide of Nef and was named SIVcpz-tNef. We found that the SIVcpz-tNef does not behave as a classic nef-deleted HIV-1 or simian immunodeficiency virus of macaques SIVmac. Markedly, SIVcpz-tNef progeny from both Hek-293T and Molt producer cells were completely non-infectious. Moreover, the loss in infectivity of SIVcpz-tNef correlated with the inhibition of Gag and GagPol processing. A marked accumulation of Gag and very low levels of reverse transcriptase were detected in viral lysates. Furthermore, these observations were reproduced once the tNef peptide was expressed in trans both in SIVcpzΔNef and HIV-1WT expressing cells, demonstrating that the truncated peptide is a dominant negative for viral processing and infectivity for both SIVcpz and HIV-1. We demonstrated that the truncated Nef peptide binds to GagPol outside the protease region and by doing so probably blocks processing of both GagPol and Gag precursors at a very early stage. This study demonstrates for the first time that naturally-occurring Nef peptides can potently block lentiviral processing and infectivity.
[Mh] Termos MeSH primário: Produtos do Gene nef/metabolismo
HIV-1/fisiologia
Vírus da Imunodeficiência Símia/fisiologia
Replicação Viral
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Mutação da Fase de Leitura
Técnicas de Inativação de Genes
Produtos do Gene gag/metabolismo
Produtos do Gene nef/genética
Produtos do Gene pol/metabolismo
Seres Humanos
Pan troglodytes
Ligação Proteica
Vírus da Imunodeficiência Símia/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gene Products, gag); 0 (Gene Products, nef); 0 (Gene Products, pol)
[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:160712
[St] Status:MEDLINE


  6 / 1280 MEDLINE  
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[PMID]:26886938
[Au] Autor:Guerra-Pérez N; Aravantinou M; Veglia F; Goode D; Truong R; Derby N; Blanchard J; Grasperge B; Gettie A; Robbiani M; Martinelli E
[Ad] Endereço:Center for Biomedical Research, Population Council, New York, New York, United States of America.
[Ti] Título:Rectal HSV-2 Infection May Increase Rectal SIV Acquisition Even in the Context of SIVΔnef Vaccination.
[So] Source:PLoS One;11(2):e0149491, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prevalent HSV-2 infection increases the risk of HIV acquisition both in men and women even in asymptomatic subjects. Understanding the impact of HSV-2 on the mucosal microenvironment may help to identify determinants of susceptibility to HIV. Vaginal HSV-2 infection increases the frequency of cells highly susceptible to HIV in the vaginal tissue of women and macaques and this correlates with increased susceptibility to vaginal SHIV infection in macaques. However, the effect of rectal HSV-2 infection on HIV acquisition remains understudied. We developed a model of rectal HSV-2 infection in macaques in combination with rectal SIVmac239Δnef (SIVΔnef) vaccination and our results suggest that rectal HSV-2 infection may increase the susceptibility of macaques to rectal SIVmac239 wild-type (wt) infection even in SIVΔnef-infected animals. Rectal SIVΔnef infection/vaccination protected 7 out of 7 SIVΔnef-infected macaques from SIVmac239wt rectal infection (vs 12 out of 16 SIVΔnef-negative macaques), while 1 out of 3 animals co-infected with SIVΔnef and HSV-2 acquired SIVmac239wt infection. HSV-2/SIVmac239wt co-infected animals had increased concentrations of inflammatory factors in their plasma and rectal fluids and a tendency toward higher acute SIVmac239wt plasma viral load. However, they had higher blood CD4 counts and reduced depletion of CCR5+ CD4+ T cells compared to SIVmac239wt-only infected animals. Thus, rectal HSV-2 infection generates a pro-inflammatory environment that may increase susceptibility to rectal SIV infection and may impact immunological and virological parameters during acute SIV infection. Studies with larger number of animals are needed to confirm these findings.
[Mh] Termos MeSH primário: Produtos do Gene nef/metabolismo
Herpesvirus Humano 2/fisiologia
Reto/virologia
Síndrome de Imunodeficiência Adquirida dos Símios/imunologia
Síndrome de Imunodeficiência Adquirida dos Símios/virologia
Vírus da Imunodeficiência Símia/fisiologia
Vacinação
[Mh] Termos MeSH secundário: Animais
Contagem de Linfócito CD4
Coinfecção/sangue
Coinfecção/imunologia
Coinfecção/virologia
Citocinas/metabolismo
Seres Humanos
Inflamação/patologia
Linfonodos/patologia
Macaca mulatta
Masculino
Fenótipo
Síndrome de Imunodeficiência Adquirida dos Símios/sangue
Carga Viral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cytokines); 0 (Gene Products, nef)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170520
[Lr] Data última revisão:
170520
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160218
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0149491


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[PMID]:26416734
[Au] Autor:Rosa A; Chande A; Ziglio S; De Sanctis V; Bertorelli R; Goh SL; McCauley SM; Nowosielska A; Antonarakis SE; Luban J; Santoni FA; Pizzato M
[Ad] Endereço:University of Trento, Centre for Integrative Biology, 38123 Trento, Italy.
[Ti] Título:HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation.
[So] Source:Nature;526(7572):212-7, 2015 Oct 08.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:HIV-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor.
[Mh] Termos MeSH primário: HIV-1/fisiologia
Interações Hospedeiro-Patógeno
Proteínas de Membrana/antagonistas & inibidores
Proteínas de Membrana/metabolismo
Vírion/química
Vírion/metabolismo
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Membrana Celular/metabolismo
Membrana Celular/virologia
Endossomos/química
Endossomos/metabolismo
Evolução Molecular
Produtos do Gene gag/metabolismo
Produtos do Gene nef/química
Produtos do Gene nef/metabolismo
HIV-1/química
Especificidade de Hospedeiro
Seres Humanos
Vírus da Leucemia Murina/química
Vírus da Leucemia Murina/fisiologia
Proteínas de Membrana/análise
Proteínas de Neoplasias/metabolismo
Primatas/virologia
Receptores de Superfície Celular/metabolismo
Proteínas rab de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Gene Products, gag); 0 (Gene Products, nef); 0 (Membrane Proteins); 0 (Neoplasm Proteins); 0 (Receptors, Cell Surface); 0 (SERINC3 protein, human); 0 (SERINC5 protein, human); 0 (nef Gene Products, Human Immunodeficiency Virus); 152989-05-4 (rab7 protein); EC 3.6.5.2 (rab GTP-Binding Proteins)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150930
[St] Status:MEDLINE
[do] DOI:10.1038/nature15399


  8 / 1280 MEDLINE  
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[PMID]:26318034
[Au] Autor:Katkoori VR; Basson MD; Bond VC; Manne U; Bumpers HL
[Ad] Endereço:Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA.
[Ti] Título:Nef-M1, a peptide antagonist of CXCR4, inhibits tumor angiogenesis and epithelial­to­mesenchymal transition in colon and breast cancers.
[So] Source:Oncotarget;6(29):27763-77, 2015 Sep 29.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Nef-M1 peptide competes effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in colon cancer (CRC) and breast cancer (BC). Its role in tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) regulation, key steps involved in tumor growth and metastasis, are unknown. We evaluated the angioinhibitory effect of Nef-M1 peptide and examined its role in the inhibition of EMT in these cancers. Colon (HT29) and breast (MDA-MB231) cancer cells expressing CXCR4 were studied in vitro and in xenograft tumors propagated in severe combined immunodeficient mice. The mice were treated intraperitoneally with Nef-M1 or scrambled amino acid sequence of Nef-M1 (sNef-M1) peptide, a negative control, starting at the time of tumor implantation. Sections from tumors were evaluated for tumor angiogenesis, as measured by microvessel density (MVD) based on immunostaining of endothelial markers. In vitro tumor angiogenesis was assessed by treating human umbilical vein endothelial cells with conditioned media from the tumor cell lines. A BC cell line (MDA-MB 468) which does not express CXCR4 was used to study the actions of Nef-M1 peptide. Western blot and immunofluorescence analyses assessed the effect of Nef-M1 on tumor angiogenesis and EMT in both tumors and cancer cells. Metastatic lesions of CRC and BC expressed more CXCR4 than primary lesions. It was also found that tumors from mice treated with sNef-M1 had well established vascularity, while Nef-M1 treated tumors had very poor vascularization. Indeed, the mean MVD was lower in tumors from Nef-M1 treated mice than in sNef-M1 treated tumors. Nef-M1 treated tumor has poor morphology and loss of endothelial integrity. Although conditioned medium from CRC or BC cells supported HUVEC tube formation, the conditioned medium from Nef-M1 treated CRC or BC cells did not support tube formation. Western blot analyses revealed that Nef-M1 effectively suppressed the expression of VEGF-A in CRC and BC cells and tumors. This suggests that Nef-M1 treated CRC and BC cells are more consistent with E-cadherin signature, and thus appears more epithelial in nature. Our data indicate that Nef-M1 peptide inhibits tumor angiogenesis and the oncogenic EMT process. Targeting the chemokine receptor, CXCR4, mediated pathways using Nef-M1 may prove to be a novel therapeutic approach for CRC and BC.
[Mh] Termos MeSH primário: Neoplasias da Mama/patologia
Neoplasias do Colo/patologia
Transição Epitelial-Mesenquimal
Produtos do Gene nef/química
Neovascularização Patológica
Fragmentos de Peptídeos/química
Peptídeos/química
Receptores CXCR4/antagonistas & inibidores
Receptores CXCR4/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Linhagem Celular Tumoral
Proliferação Celular
Meios de Cultivo Condicionados/metabolismo
Progressão da Doença
Ensaio de Imunoadsorção Enzimática
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Camundongos
Camundongos SCID
Microcirculação
Metástase Neoplásica
Transplante de Neoplasias
Molécula-1 de Adesão Celular Endotelial de Plaquetas/metabolismo
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (CXCR4 protein, human); 0 (Culture Media, Conditioned); 0 (Gene Products, nef); 0 (Peptide Fragments); 0 (Peptides); 0 (Platelet Endothelial Cell Adhesion Molecule-1); 0 (Receptors, CXCR4); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150831
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.4615


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[PMID]:26041873
[Au] Autor:Nakano Y; Matsuda K; Yoshikawa R; Yamada E; Misawa N; Hirsch VM; Koyanagi Y; Sato K
[Ad] Endereço:1​Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto 6068507, Japan 2​Department of Medical Virology, Faculty of Life Sciences, Kumamoto University, Kumamoto 8608556, Japan.
[Ti] Título:Down-modulation of primate lentiviral receptors by Nef proteins of simian immunodeficiency virus (SIV) of chimpanzees (SIVcpz) and related SIVs: implication for the evolutionary event at the emergence of SIVcpz.
[So] Source:J Gen Virol;96(9):2867-77, 2015 Sep.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It has been estimated that human immunodeficiency virus type 1 originated from the zoonotic transmission of simian immunodeficiency virus (SIV) of chimpanzees, SIVcpz, and that SIVcpz emerged by the recombination of two lineages of SIVs in Old World monkeys (SIVgsn/mon/mus in guenons and SIVrcm in red-capped mangabeys) and SIVcpz Nef is most closely related to SIVrcm Nef. These observations suggest that SIVrcm Nef had an advantage over SIVgsn/mon/mus during the evolution of SIVcpz in chimpanzees, although this advantage remains uncertain. Nef is a multifunctional protein which downregulates CD4 and coreceptor proteins from the surface of infected cells, presumably to limit superinfection. To assess the possibility that SIVrcm Nef was selected by its superior ability to downregulate viral entry receptors in chimpanzees, we compared its ability to down-modulate viral receptor proteins from humans, chimpanzees and red-capped mangabeys with Nef proteins from eight other different strains of SIVs. Surprisingly, the ability of SIVrcm Nef to downregulate CCR5, CCR2B and CXCR6 was comparable to or lower than SIVgsn/mon/mus Nef, indicating that ability to down-modulate chemokine receptors was not the selective pressure. However, SIVrcm Nef significantly downregulates chimpanzee CD4 over SIVgsn/mon/mus Nefs. Our findings suggest the possibility that the selection of SIVrcm Nef by ancestral SIVcpz is due to its superior capacity to down-modulate chimpanzees CD4 rather than coreceptor proteins.
[Mh] Termos MeSH primário: Evolução Molecular
Produtos do Gene nef/genética
Lentivirus de Primatas/genética
Doenças dos Primatas/genética
Receptores Virais/genética
Síndrome de Imunodeficiência Adquirida dos Símios/genética
Vírus da Imunodeficiência Símia/genética
[Mh] Termos MeSH secundário: Animais
Cercocebus
Produtos do Gene nef/metabolismo
Interações Hospedeiro-Patógeno
Seres Humanos
Lentivirus de Primatas/classificação
Lentivirus de Primatas/metabolismo
Pan troglodytes
Filogenia
Doenças dos Primatas/metabolismo
Doenças dos Primatas/virologia
Primatas
Receptores Virais/metabolismo
Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo
Síndrome de Imunodeficiência Adquirida dos Símios/virologia
Vírus da Imunodeficiência Símia/classificação
Vírus da Imunodeficiência Símia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Gene Products, nef); 0 (Receptors, Virus)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:160901
[Lr] Data última revisão:
160901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150605
[St] Status:MEDLINE
[do] DOI:10.1099/vir.0.000207


  10 / 1280 MEDLINE  
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[PMID]:25423108
[Au] Autor:de Carvalho JV; de Castro RO; da Silva EZ; Silveira PP; da Silva-Januário ME; Arruda E; Jamur MC; Oliver C; Aguiar RS; daSilva LL
[Ad] Endereço:Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
[Ti] Título:Nef neutralizes the ability of exosomes from CD4+ T cells to act as decoys during HIV-1 infection.
[So] Source:PLoS One;9(11):e113691, 2014.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nef is an HIV-1 accessory protein that promotes viral replication and pathogenesis. A key function of Nef is to ensure sustained depletion of CD4 and MHC-I molecules in infected cells by inducing targeting of these proteins to multivesicular bodies (MVBs), and ultimately to lysosomes for degradation. Nef also affects cellular secretory routes promoting its own secretion via exosomes. To better understand the effects of Nef on the exocytic pathway, we investigated whether this viral factor modifies the composition of exosomes released by T lymphocytes. We showed that both CD4 and MHC-I molecules are secreted in exosomes from T cells and that the expression of Nef reduces the amount of these proteins in exosomes. To investigate the functional role for this novel activity of Nef, we performed in vitro HIV-1 infection assays in the presence of distinct populations of exosomes. We demonstrated that exosomes released by CD4+ T cells, but not CD4- T cells, efficiently inhibit HIV-1 infection in vitro. Because CD4 is the main receptor for HIV-1 infection, these results suggest that CD4 molecules displayed on the surface of exosomes can bind to envelope proteins of HIV-1 hindering virus interaction with target cells and infection. Importantly, CD4-depleted exosomes released by CD4+ T cells expressing Nef have a reduced capacity to inhibit HIV-1 infection in vitro. These results provide evidence that Nef promotes HIV-1 infection by reducing the expression of CD4 in exosomes from infected cells, besides the original role of Nef in reducing the CD4 levels at the cell surface.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Exossomos/imunologia
Produtos do Gene nef/imunologia
Infecções por HIV/imunologia
[Mh] Termos MeSH secundário: Linhagem Celular
Regulação para Baixo
Células HEK293
HIV-1
Seres Humanos
Complexo Principal de Histocompatibilidade/imunologia
Microscopia de Fluorescência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Gene Products, nef)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:151028
[Lr] Data última revisão:
151028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141126
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0113691



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