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[PMID]:28743825
[Au] Autor:Navarro Negredo P; Edgar JR; Wrobel AG; Zaccai NR; Antrobus R; Owen DJ; Robinson MS
[Ad] Endereço:Cambridge Institute for Medical Research, University of Cambridge, Cambridge, England, UK.
[Ti] Título:Contribution of the clathrin adaptor AP-1 subunit µ1 to acidic cluster protein sorting.
[So] Source:J Cell Biol;216(9):2927-2943, 2017 Sep 04.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acidic clusters act as sorting signals for packaging cargo into clathrin-coated vesicles (CCVs), and also facilitate down-regulation of MHC-I by HIV-1 Nef. To find acidic cluster sorting machinery, we performed a gene-trap screen and identified the medium subunit (µ1) of the clathrin adaptor AP-1 as a top hit. In µ1 knockout cells, intracellular CCVs still form, but acidic cluster proteins are depleted, although several other CCV components were either unaffected or increased, indicating that cells can compensate for long-term loss of AP-1. In vitro experiments showed that the basic patch on µ1 that interacts with the Nef acidic cluster also contributes to the binding of endogenous acidic cluster proteins. Surprisingly, µ1 mutant proteins lacking the basic patch and/or the tyrosine-based motif binding pocket could rescue the µ1 knockout phenotype completely. In contrast, these mutants failed to rescue Nef-induced down-regulation of MHC class I, suggesting a possible mechanism for attacking the virus while sparing the host cell.
[Mh] Termos MeSH primário: Complexo 1 de Proteínas Adaptadoras/metabolismo
Subunidades mu do Complexo de Proteínas Adaptadoras/metabolismo
Vesículas Revestidas por Clatrina/metabolismo
HIV-1/metabolismo
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Complexo 1 de Proteínas Adaptadoras/química
Complexo 1 de Proteínas Adaptadoras/genética
Subunidades mu do Complexo de Proteínas Adaptadoras/química
Subunidades mu do Complexo de Proteínas Adaptadoras/genética
Sistemas CRISPR-Cas
Citometria de Fluxo
Técnicas de Silenciamento de Genes
Genótipo
Células HEK293
HIV-1/genética
Células HeLa
Antígenos de Histocompatibilidade Classe I/genética
Antígenos de Histocompatibilidade Classe I/metabolismo
Interações Hospedeiro-Patógeno
Seres Humanos
Modelos Moleculares
Mutação
Fenótipo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Transporte Proteico
Relação Estrutura-Atividade
Fatores de Tempo
Transfecção
Produtos do Gene nef do Vírus da Imunodeficiência Humana/química
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP1M1 protein, human); 0 (Adaptor Protein Complex 1); 0 (Adaptor Protein Complex mu Subunits); 0 (Histocompatibility Antigens Class I); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201602058


  2 / 1597 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


  3 / 1597 MEDLINE  
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[PMID]:28931091
[Au] Autor:Thomas AS; Jones KL; Gandhi RT; McMahon DK; Cyktor JC; Chan D; Huang SH; Truong R; Bosque A; Macedo AB; Kovacs C; Benko E; Eron JJ; Bosch RJ; Lalama CM; Simmens S; Walker BD; Mellors JW; Jones RB
[Ad] Endereço:Department of Microbiology Immunology and Tropical Medicine, George Washington University, Washington, District of Columbia, United States of America.
[Ti] Título:T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.
[So] Source:PLoS Pathog;13(9):e1006629, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/imunologia
Infecções por HIV/imunologia
Latência Viral/imunologia
Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia
[Mh] Termos MeSH secundário: Antirretrovirais/uso terapêutico
ELISPOT
Infecções por HIV/tratamento farmacológico
Seres Humanos
Reação em Cadeia da Polimerase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Retroviral Agents); 0 (nef Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006629


  4 / 1597 MEDLINE  
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[PMID]:28659343
[Au] Autor:Trautz B; Wiedemann H; Lüchtenborg C; Pierini V; Kranich J; Glass B; Kräusslich HG; Brocker T; Pizzato M; Ruggieri A; Brügger B; Fackler OT
[Ad] Endereço:From the Department of Infectious Diseases, Integrative Virology, and.
[Ti] Título:The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles.
[So] Source:J Biol Chem;292(33):13702-13713, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The host-cell restriction factor SERINC5 potently suppresses the infectivity of HIV, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which SERINC5 restricts HIV-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of HIV particles is a major determinant of the infectious potential of the particles, we tested whether SERINC5-mediated restriction of HIV particle infectivity involves alterations of membrane lipid composition. We produced and purified HIV-1 particles from SERINC5293T cells with very low endogenous SERINC5 levels under conditions in which ectopically expressed SERINC5 restricts HIV-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS. SERINC5 restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and HIV particles. Sphingosine metabolism kinetics were also unaltered by SERINC5 expression. Moreover, the levels of phosphatidylserine on the surface of HIV-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of SERINC5 or Nef. Finally, saturating the phosphatidylserine-binding sites on HIV target cells did not affect SERINC5 restriction or Nef antagonism. These results demonstrate that the restriction of HIV-1 particle infectivity by SERINC5 does not depend on alterations in lipid composition and organization of HIV-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of SERINC5.
[Mh] Termos MeSH primário: HIV-1/patogenicidade
Metabolismo dos Lipídeos
Proteínas de Membrana/metabolismo
Vírion/patogenicidade
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Antígenos de Superfície/genética
Antígenos de Superfície/metabolismo
Ligação Competitiva
Linhagem Celular Tumoral
Deleção de Genes
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HEK293
HIV-1/química
HIV-1/fisiologia
Seres Humanos
Cinética
Lipossomos
Proteínas de Membrana/antagonistas & inibidores
Proteínas de Membrana/genética
Proteínas do Leite/genética
Proteínas do Leite/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Fosfatidilserinas/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Esfingosina/metabolismo
Propriedades de Superfície
Vírion/química
Vírion/fisiologia
Montagem de Vírus
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Surface); 0 (Liposomes); 0 (MFGE8 protein, human); 0 (Membrane Proteins); 0 (Milk Proteins); 0 (Peptide Fragments); 0 (Phosphatidylserines); 0 (Recombinant Fusion Proteins); 0 (SERINC5 protein, human); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1); 147336-22-9 (Green Fluorescent Proteins); NGZ37HRE42 (Sphingosine)
[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
[do] DOI:10.1074/jbc.M117.797332


  5 / 1597 MEDLINE  
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[PMID]:28615199
[Au] Autor:Alsahafi N; Richard J; Prévost J; Coutu M; Brassard N; Parsons MS; Kaufmann DE; Brockman M; Finzi A
[Ad] Endereço:Centre de Recherche du CHUM, Montreal, QC, Canada.
[Ti] Título:Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity.
[So] Source:J Virol;91(16), 2017 Aug 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-1 Nef clones isolated from a rare subset of HIV-1-infected elite controllers (EC), with the ability to suppress viral load to undetectable levels in the absence of antiretroviral therapy, are unable to fully downregulate CD4 from the plasma membrane of CD4 T cells. Residual CD4 left at the plasma membrane allows Env-CD4 interaction, which leads to increased exposure of Env CD4-induced epitopes and increases susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated largely by natural killer (NK) cells, which control their activation status through the cumulative signals received through activating and inhibitory receptors. Recently, the activating NKG2D receptor was demonstrated to positively influence ADCC responses. Since HIV-1 Nef has been reported to reduce the expression of NKG2D ligands, we evaluated the relative abilities of Nef from EC and progressors to downmodulate NKG2D ligands. Furthermore, we assessed the impact of EC and progressor Nef on the ADCC susceptibility of HIV-1-infected cells. We observed a significantly increased expression of NKG2D ligands on cells infected with viruses coding for Nef from EC. Importantly, NKG2D ligand expression levels correlated with enhanced susceptibility of HIV-1-infected cells to ADCC. The biological significance of this correlation was corroborated by the demonstration that antibody-mediated blockade of NKG2D significantly reduced ADCC of cells infected with viruses carrying Nef from EC. These results suggest the involvement of NKG2D-NKG2D ligand interactions in the enhanced susceptibility of EC HIV-1-infected cells to ADCC responses. Attenuated Nef functions have been reported in HIV-1 isolated from EC. The inability of elite controller Nef to fully remove CD4 from the surface of infected cells enhanced their susceptibility to elimination by ADCC. We now show that downregulation of NKG2D ligands by HIV-1 Nef from EC is inefficient and leaves infected cells susceptible to ADCC. These data suggest a critical role for NKG2D ligands in anti-HIV-1 ADCC responses.
[Mh] Termos MeSH primário: Citotoxicidade Celular Dependente de Anticorpos
Infecções por HIV/imunologia
HIV-1/fisiologia
Interações Hospedeiro-Patógeno
Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Sobreviventes de Longo Prazo ao HIV
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KLRK1 protein, human); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170810
[Lr] Data última revisão:
170810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE


  6 / 1597 MEDLINE  
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[PMID]:28577469
[Au] Autor:Jacob RA; Johnson AL; Pawlak EN; Dirk BS; Van Nynatten LR; Haeryfar SMM; Dikeakos JD
[Ad] Endereço:Department of Microbiology and Immunology, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
[Ti] Título:The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4 T cell apoptosis.
[So] Source:Virology;509:1-10, 2017 Sep.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acquired Immune Deficiency Syndrome is characterized by a decline in CD4 T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4 T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (Nef or Nef ) or Nef:AP-2 (Nef ), implying these interactions limit Nef-mediated apoptosis. In contrast, disrupting the Nef:PAK2 interaction motifs (Nef or Nef ) reduced apoptosis. To validate further, apoptosis was measured after short-hairpin RNA knock-down of AP-1, AP-2 and PAK2. AP-2α depletion enhanced apoptosis, demonstrating that disrupting the Nef:AP-2α interaction limits Nef-mediated apoptosis. Collectively, we describe a mechanism by which HIV-1 regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions.
[Mh] Termos MeSH primário: Complexo 2 de Proteínas Adaptadoras/metabolismo
Apoptose
Linfócitos T CD4-Positivos/fisiologia
Linfócitos T CD4-Positivos/virologia
HIV-1/patogenicidade
Interações Hospedeiro-Patógeno
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Análise Mutacional de DNA
Seres Humanos
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex 2); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE


  7 / 1597 MEDLINE  
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[PMID]:28275190
[Au] Autor:Zhang X; Zhou T; Yang J; Lin Y; Shi J; Zhang X; Frabutt DA; Zeng X; Li S; Venta PJ; Zheng YH
[Ad] Endereço:Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China.
[Ti] Título:Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction.
[So] Source:J Virol;91(10), 2017 May 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Among the five serine incorporator (SERINC) family members, SERINC5 (Ser5) was reported to strongly inhibit HIV-1 replication, which is counteracted by Nef. produces 5 alternatively spliced isoforms: Ser5-001 has 10 putative transmembrane domains, whereas Ser5-004, -005, -008a, and -008b do not have the last one. Here, we confirmed the strong Ser5 anti-HIV-1 activity and investigated its isoforms' expression and antiviral activities. It was found that transcripts were detected at least 10-fold more than the other isoforms by real-time quantitative PCR. When Ser5-001 and its two isoforms Ser5-005 and Ser5-008a were expressed from the same mammalian expression vector, only Ser5-001 was stably expressed, whereas the others were poorly expressed due to rapid degradation. In addition, unlike the other isoforms, which are located mainly in the cytoplasm, Ser5-001 is localized primarily to the plasma membrane. To map the critical determinant, Ser5 mutants bearing C-terminal deletions were created. It was found that the 10th transmembrane domain is required for Ser5 stable expression and plasma membrane localization. As expected, only Ser5-001 strongly inhibits HIV-1 infectivity, whereas the other Ser5 isoforms and mutants that do not have the 10th transmembrane domain show very poor activity. It was also observed that the Nef counteractive activity could be easily saturated by Ser5 overexpression. Thus, we conclude that Ser5-001 is the predominant antiviral isoform that restricts HIV-1, and the 10th transmembrane domain plays a critical role in this process by regulating its protein stability and plasma membrane targeting. Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) express a small protein, Nef, to enhance viral pathogenesis Nef has an important function, which is to make virus particles more infectious, but the mechanism has been unclear. Recently, Nef was reported to counteract a novel anti-HIV host protein, SERINC5 (Ser5). Ser5 has five alternatively spliced isoforms, Ser5-001, -004, -005, -008a, and -008b, and only Ser5-001 has an extra C-terminal transmembrane domain. We now show that the Ser5-001 transcripts are produced at least 10-fold more than the others, and only Ser5-001 produces stable proteins that are targeted to the plasma membrane. Importantly, only Ser5-001 shows strong anti-HIV-1 activity. We further demonstrate that the extra transmembrane domain is required for Ser5 stable expression and plasma membrane localization. These results suggest that plasma membrane localization is required for Ser5 antiviral activity, and Ser5-001 is the predominant isoform that contributes to the activity.
[Mh] Termos MeSH primário: HIV-1/fisiologia
Interações Hospedeiro-Patógeno
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
[Mh] Termos MeSH secundário: Animais
HIV-1/genética
Seres Humanos
Proteínas de Membrana/química
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Isoformas de Proteínas
Processamento de RNA
Receptores de Superfície Celular/genética
Receptores de Superfície Celular/metabolismo
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Proteins); 0 (Neoplasm Proteins); 0 (Protein Isoforms); 0 (Receptors, Cell Surface); 0 (SERINC3 protein, human); 0 (SERINC5 protein, human); 0 (nef Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


  8 / 1597 MEDLINE  
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[PMID]:28179429
[Au] Autor:Sood C; Marin M; Chande A; Pizzato M; Melikyan GB
[Ad] Endereço:From the Department of Pediatrics, Emory University, Atlanta, Georgia 30322 and.
[Ti] Título:SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins.
[So] Source:J Biol Chem;292(14):6014-6026, 2017 Apr 07.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells, an effect that is antagonized by the viral Nef protein. Envelope (Env) glycoproteins from different HIV-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with HIV-1 fusion remains unclear. Here, we show that incorporation of SERINC5 into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells. Strikingly, we found that SERINC5 promotes spontaneous functional inactivation of sensitive but not resistant Env glycoproteins. Although SERINC5-Env interaction was not detected by co-immunoprecipitation, incorporation of this protein enhanced the exposure of the conserved gp41 domains and sensitized the virus to neutralizing antibodies and gp41-derived inhibitory peptides. These results imply that SERINC5 restricts HIV-1 fusion at a step prior to small pore formation by selectively inactivating sensitive Env glycoproteins, likely through altering their conformation. The increased HIV-1 sensitivity to anti-gp41 antibodies and peptides suggests that SER5 also delays refolding of the remaining fusion-competent Env trimers.
[Mh] Termos MeSH primário: Proteína gp41 do Envelope de HIV/metabolismo
HIV-1/metabolismo
Proteínas de Membrana/metabolismo
Redobramento de Proteína
[Mh] Termos MeSH secundário: Células HEK293
Anticorpos Anti-HIV/farmacologia
Proteína gp41 do Envelope de HIV/genética
HIV-1/genética
Seres Humanos
Proteínas de Membrana/genética
Domínios Proteicos
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Antibodies); 0 (HIV Envelope Protein gp41); 0 (Membrane Proteins); 0 (SERINC5 protein, human); 0 (gp41 protein, Human immunodeficiency virus 1); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.777714


  9 / 1597 MEDLINE  
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[PMID]:28079886
[Au] Autor:Sami Saribas A; Cicalese S; Ahooyi TM; Khalili K; Amini S; Sariyer IK
[Ad] Endereço:Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine, Temple University, Philadelphia, 19140 PA, USA.
[Ti] Título:HIV-1 Nef is released in extracellular vesicles derived from astrocytes: evidence for Nef-mediated neurotoxicity.
[So] Source:Cell Death Dis;8(1):e2542, 2017 Jan 12.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Human immunodeficiency virus-associated neurological disorders (HANDs) affect the majority of AIDS patients and are a significant problem among HIV-1-infected individuals who live longer because of combined anti-retroviral therapies. HIV-1 utilizes a number of viral proteins and subsequent cytokine inductions to unleash its toxicity on neurons. Among HIV-1 viral proteins, Nef is a small protein expressed abundantly in astrocytes of HIV-1-infected brains and has been suggested to have a role in the pathogenesis of HAND. In order to explore its effect in the central nervous system, HIV-1 Nef was expressed in primary human fetal astrocytes (PHFAs) using an adenovirus. Our results revealed that HIV-1 Nef is released in extracellular vesicles (EVs) derived from PHFA cells expressing the protein. Interestingly, HIV-1 Nef release in EVs was enriched significantly when the cells were treated with autophagy activators perifosine, tomaxifen, MG-132, and autophagy inhibitors LY294002 and wortmannin suggesting a novel role of autophagy signaling in HIV-1 Nef release from astrocytes. Next, Nef-carrying EVs were purified from astrocyte cultures and neurotoxic effects on neurons were analyzed. We observed that HIV-1 Nef-containing EVs were readily taken up by neurons as demonstrated by immunocytochemistry and immunoblotting. Furthermore, treatment of neurons with Nef-carrying EVs induced oxidative stress as evidenced by a decrease in glutathione levels. To further investigate its neurotoxic effects, we expressed HIV-1 Nef in primary neurons by adenoviral transduction. Intracellular expression of HIV-1 Nef caused axonal and neurite degeneration of neurons. Furthermore, expression of HIV-1 Nef decreased the levels of phospho-tau while enhancing total tau in primary neurons. In addition, treatment of primary neurons with Nef-carrying EVs suppressed functional neuronal action potential assessed by multielectrode array studies. Collectively, these data suggested that HIV-1 Nef can be a formidable contributor to neurotoxicity along with other factors, which leads to HAND in HIV-1-infected AIDS patients.
[Mh] Termos MeSH primário: Vesículas Extracelulares/genética
Infecções por HIV/tratamento farmacológico
Infecções por HIV/genética
Síndromes Neurotóxicas/genética
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
[Mh] Termos MeSH secundário: Astrócitos/efeitos dos fármacos
Astrócitos/metabolismo
Astrócitos/virologia
Autofagia/efeitos dos fármacos
Autofagia/genética
Vesículas Extracelulares/virologia
Feto/virologia
Infecções por HIV/complicações
Infecções por HIV/virologia
HIV-1/efeitos dos fármacos
HIV-1/patogenicidade
Seres Humanos
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Neurônios/virologia
Síndromes Neurotóxicas/tratamento farmacológico
Síndromes Neurotóxicas/etiologia
Síndromes Neurotóxicas/virologia
Cultura Primária de Células
Produtos do Gene nef do Vírus da Imunodeficiência Humana/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (nef Gene Products, Human Immunodeficiency Virus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170113
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2016.467


  10 / 1597 MEDLINE  
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[PMID]:28076321
[Au] Autor:Huang MB; Gonzalez RR; Lillard J; Bond VC
[Ad] Endereço:Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, 30310, USA.
[Ti] Título:Secretion modification region-derived peptide blocks exosome release and mediates cell cycle arrest in breast cancer cells.
[So] Source:Oncotarget;8(7):11302-11315, 2017 Feb 14.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Discovery and development of a novel anticancer PEG-SMR-Clu peptide to prevent breast cancer metastasis. How breast cancer cells and primary mammary epithelial cells interact and communicate with each other to promote tumorigenesis and how to prevent tumor metastasis has long been a concern of researchers. Cancer cells secrete exosomes containing proteins and RNA. These factors can influence tumor development by directly targeting cancer cells and tumor stroma. In this study, we determined the effects of a peptide as an inhibitor of exosome secretion on breast tumors. We developed a peptide derived from the Secretion Modification Region (SMR) of HIV-1 Nef protein that was modified with PEG on the N-terminus and with a Clusterin (Clu)-binding peptide on the C-terminus. Attachment of PEG to the SMR peptide, termed PEGylation, offers improved water solubility and stability as well as reduced clearance through the kidneys, leading to a longer circulation time. The 12-mer Clu-binding peptide plays multiple roles in tumor development and metastasis. The Clu peptide can be detected by antibody in vivo, thus it has the potential to be used to monitor tumor status and treatment efficacy in animal studies and eventually in cancer patients. RESULTS: PEG-SMRwt-Clu and PEG-SMRwt peptides inhibited the growth of both of MCF-7 (estrogen responsive, ER+) and MDA-MD-231 (estrogen non-responsive, ER-) human breast cancer cells in a dose and time-dependent manner, without inducing cytotoxic effects. The SMRwt peptide, combined with paclitaxel, induced G2/M phase cell cycle arrest on MCF-7 and MDA-MB-231 cells but did not promote apoptosis. PEG-SMRwt-Clu peptide treatment blocked exosome release from both MCF-7 and MDA-MB-231 cells. This effect was blocked by knockdown of the chaperone protein mortalin by either antibody or siRNA. MATERIALS AND METHODS: MCF-7 and MDA-MB-231 breast tumor cells were treated with PEG-SMR-Clu peptide alone and in combination with paclitaxel and cisplatin. Cell proliferation and viabilty were determined via cell cycle analysis using Cellometer imaging cytometry, Annexin V and MTT assays. The effects of the PEG-SMR-Clu peptide on tumor exosome release were determined by testing isolated exosome fractions, for (i) expression of CD63 and Alix proteins by Western blotting, (ii) NanoSight nanoparticle tracking analysis (NTA 10) to measure exosomes size and concentration, and (iii) measurement of acetylcholinesterase (AchE) for exosome specific enzyme activity. CONCLUSIONS: PEG-SMRwt-CLU peptides inhibited the growth of human breast cancer cells and blocked tumor exosome release in vitro. The peptide alone did not cause increased cytotoxicity or apoptosis induction, but did cause cell cycle G2/M phase arrest in both estrogen responsive and non-responsive breast cancer cells. These data suggest a potential therapeutic value of SMR to prevent breast cancer metastasis and as an adjuvant for the chemotherapeutic treatment of human breast cancer.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias da Mama/patologia
Clusterina/farmacologia
Exossomos/secreção
Peptídeos/farmacologia
Produtos do Gene nef do Vírus da Imunodeficiência Humana/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Western Blotting
Neoplasias da Mama/metabolismo
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Feminino
Seres Humanos
Polietilenoglicóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Clusterin); 0 (Peptides); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1); 30IQX730WE (Polyethylene Glycols)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171117
[Lr] Data última revisão:
171117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14513



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