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  1. Article: A Conserved Tryptophan in the Envelope Cytoplasmic Tail Regulates HIV-1 Assembly and Spread

    Snetkov, Xenia / Haider, Tafhima / Mesner, Dejan / Groves, Nicholas / van Engelenburg, Schuyler B. / Jolly, Clare

    Viruses. 2022 Jan. 12, v. 14, no. 1

    2022  

    Abstract: The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains ... ...

    Abstract The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains within it remain largely uncharacterised. Here, we identified a highly conserved tryptophan motif at position 757 (W757) in the LLP-2 alpha helix of the EnvCT as a key determinant for HIV-1 replication and spread between T cells. Alanine substitution at this position potently inhibited HIV-1 cell–cell spread (the dominant mode of HIV-1 dissemination) by preventing recruitment of Env and Gag to sites of cell–cell contact, inhibiting virological synapse (VS) formation and spreading infection. Single-molecule tracking and super-resolution imaging showed that mutation of W757 dysregulates Env diffusion in the plasma membrane and increases Env mobility. Further analysis of Env function revealed that W757 is also required for Env fusion and infectivity, which together with reduced VS formation, result in a potent defect in viral spread. Notably, W757 lies within a region of the EnvCT recently shown to act as a supporting baseplate for Env. Our data support a model in which W757 plays a key role in regulating Env biology, modulating its temporal and spatial recruitment to virus assembly sites and regulating the inherent fusogenicity of the Env ectodomain, thereby supporting efficient HIV-1 replication and spread.
    Keywords alanine ; models ; mutation ; pathogenicity ; plasma membrane ; synapse ; tryptophan ; virus assembly
    Language English
    Dates of publication 2022-0112
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2516098-9
    ISSN 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v14010129
    Database NAL-Catalogue (AGRICOLA)

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  2. Article ; Online: A Conserved Tryptophan in the Envelope Cytoplasmic Tail Regulates HIV-1 Assembly and Spread.

    Snetkov, Xenia / Haider, Tafhima / Mesner, Dejan / Groves, Nicholas / van Engelenburg, Schuyler B / Jolly, Clare

    Viruses

    2022  Volume 14, Issue 1

    Abstract: The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains ... ...

    Abstract The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains within it remain largely uncharacterised. Here, we identified a highly conserved tryptophan motif at position 757 (W757) in the LLP-2 alpha helix of the EnvCT as a key determinant for HIV-1 replication and spread between T cells. Alanine substitution at this position potently inhibited HIV-1 cell-cell spread (the dominant mode of HIV-1 dissemination) by preventing recruitment of Env and Gag to sites of cell-cell contact, inhibiting virological synapse (VS) formation and spreading infection. Single-molecule tracking and super-resolution imaging showed that mutation of W757 dysregulates Env diffusion in the plasma membrane and increases Env mobility. Further analysis of Env function revealed that W757 is also required for Env fusion and infectivity, which together with reduced VS formation, result in a potent defect in viral spread. Notably, W757 lies within a region of the EnvCT recently shown to act as a supporting baseplate for Env. Our data support a model in which W757 plays a key role in regulating Env biology, modulating its temporal and spatial recruitment to virus assembly sites and regulating the inherent fusogenicity of the Env ectodomain, thereby supporting efficient HIV-1 replication and spread.
    MeSH term(s) CD4-Positive T-Lymphocytes ; Cell Membrane/metabolism ; HEK293 Cells ; HIV Envelope Protein gp41 ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/physiology ; HeLa Cells ; Humans ; T-Lymphocytes/metabolism ; T-Lymphocytes/virology ; Tryptophan/metabolism ; Virion/metabolism ; Virus Assembly/physiology ; Virus Internalization ; Virus Replication ; env Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances HIV Envelope Protein gp41 ; env Gene Products, Human Immunodeficiency Virus ; Tryptophan (8DUH1N11BX)
    Language English
    Publishing date 2022-01-12
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v14010129
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Single-molecule imaging of HIV-1 envelope glycoprotein dynamics and Gag lattice association exposes determinants responsible for virus incorporation.

    Pezeshkian, Nairi / Groves, Nicholas S / van Engelenburg, Schuyler B

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 50, Page(s) 25269–25277

    Abstract: The HIV-1 envelope glycoprotein (Env) is sparsely incorporated onto assembling virus particles on the host cell plasma membrane in order for the virus to balance infectivity and evade the immune response. Env becomes trapped in a nascent particle on ... ...

    Abstract The HIV-1 envelope glycoprotein (Env) is sparsely incorporated onto assembling virus particles on the host cell plasma membrane in order for the virus to balance infectivity and evade the immune response. Env becomes trapped in a nascent particle on encounter with the polymeric viral protein Gag, which forms a dense protein lattice on the inner leaflet of the plasma membrane. While Env incorporation efficiency is readily measured biochemically from released particles, very little is known about the spatiotemporal dynamics of Env trapping events. Herein, we demonstrate, via high-resolution single-molecule tracking, that retention of Env trimers within single virus assembly sites requires the Env cytoplasmic tail (CT) and the L12 residue in the matrix (MA) domain of Gag but does not require curvature of the viral lattice. We further demonstrate that Env trimers are confined to subviral regions of a budding Gag lattice, supporting a model where direct interactions and/or steric corralling between the Env-CT and a lattice of MA trimers promote Env trapping and infectious HIV-1 assembly.
    MeSH term(s) Cell Membrane/virology ; HIV Infections/virology ; HIV-1/chemistry ; HIV-1/genetics ; HIV-1/physiology ; Humans ; Protein Binding ; Protein Domains ; Single Molecule Imaging ; Virus Assembly ; env Gene Products, Human Immunodeficiency Virus/chemistry ; env Gene Products, Human Immunodeficiency Virus/genetics ; env Gene Products, Human Immunodeficiency Virus/metabolism ; gag Gene Products, Human Immunodeficiency Virus/chemistry ; gag Gene Products, Human Immunodeficiency Virus/genetics ; gag Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances env Gene Products, Human Immunodeficiency Virus ; gag Gene Products, Human Immunodeficiency Virus
    Language English
    Publishing date 2019-11-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1910008116
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
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  4. Article: A Quantitative Live-Cell Superresolution Imaging Framework for Measuring the Mobility of Single Molecules at Sites of Virus Assembly.

    Groves, Nicholas S / Bruns, Merissa M / van Engelenburg, Schuyler B

    Pathogens (Basel, Switzerland)

    2020  Volume 9, Issue 11

    Abstract: The insurgence of superresolution microscopy into the fields of virology and microbiology has begun to enable the mapping of molecular assemblies critical for host-pathogen interfaces that organize on a scale below the resolution limit of the light ... ...

    Abstract The insurgence of superresolution microscopy into the fields of virology and microbiology has begun to enable the mapping of molecular assemblies critical for host-pathogen interfaces that organize on a scale below the resolution limit of the light microscope. It is, however, challenging to completely understand the molecular interactions between host and pathogen from strictly time-invariant observations. Herein, we describe a method using simultaneous dual-color superresolution microscopy to gain both structural and dynamic information about HIV-1 assembly. Specifically, we demonstrate the reconstruction of single virus assembly sites using live-cell photo-activated localization microscopy (PALM) while concurrently assessing the sub-viral mobility of the HIV-1 envelope glycoprotein during interaction with the viral lattice. We propose that our method is broadly applicable to elucidating pathogen and host protein-protein interactions through quantification of the dynamics of these proteins at the nanoscale.
    Language English
    Publishing date 2020-11-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens9110972
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Endocytosed HIV-1 Envelope Glycoprotein Traffics to Rab14

    Hoffman, Huxley K / Aguilar, Rebekah S / Clark, Austin R / Groves, Nicholas S / Pezeshkian, Nairi / Bruns, Merissa M / van Engelenburg, Schuyler B

    Journal of virology

    2022  Volume 96, Issue 14, Page(s) e0076722

    Abstract: Production of infectious HIV-1 particles requires incorporation of the viral envelope glycoprotein (Env) at the plasma membrane (PM) of infected ... ...

    Abstract Production of infectious HIV-1 particles requires incorporation of the viral envelope glycoprotein (Env) at the plasma membrane (PM) of infected CD4
    MeSH term(s) Cell Line ; Endocytosis ; Endosomes/metabolism ; Endosomes/virology ; Epitopes ; HIV Infections/metabolism ; HIV-1 ; Humans ; Lysosomes/metabolism ; Lysosomes/virology ; Protein Transport ; T-Lymphocytes/virology ; env Gene Products, Human Immunodeficiency Virus/metabolism ; rab GTP-Binding Proteins/metabolism
    Chemical Substances Epitopes ; env Gene Products, Human Immunodeficiency Virus ; Rab14 protein, human (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2022-06-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.00767-22
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 609: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article: A Quantitative Live-Cell Superresolution Imaging Framework for Measuring the Mobility of Single Molecules at Sites of Virus Assembly

    Groves, Nicholas S / Bruns, Merissa M / van Engelenburg, Schuyler B

    Pathogens. 2020 Nov. 21, v. 9, no. 11

    2020  

    Abstract: The insurgence of superresolution microscopy into the fields of virology and microbiology has begun to enable the mapping of molecular assemblies critical for host–pathogen interfaces that organize on a scale below the resolution limit of the light ... ...

    Abstract The insurgence of superresolution microscopy into the fields of virology and microbiology has begun to enable the mapping of molecular assemblies critical for host–pathogen interfaces that organize on a scale below the resolution limit of the light microscope. It is, however, challenging to completely understand the molecular interactions between host and pathogen from strictly time-invariant observations. Herein, we describe a method using simultaneous dual-color superresolution microscopy to gain both structural and dynamic information about HIV-1 assembly. Specifically, we demonstrate the reconstruction of single virus assembly sites using live-cell photo-activated localization microscopy (PALM) while concurrently assessing the sub-viral mobility of the HIV-1 envelope glycoprotein during interaction with the viral lattice. We propose that our method is broadly applicable to elucidating pathogen and host protein–protein interactions through quantification of the dynamics of these proteins at the nanoscale.
    Keywords dynamics ; fields ; glycoproteins ; image analysis ; information ; light microscopes ; microscopy ; pathogens ; protein-protein interactions ; virus assembly
    Language English
    Dates of publication 2020-1121
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    Note NAL-light
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens9110972
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: Genomic tagging of endogenous human ESCRT-I complex preserves ESCRT-mediated membrane-remodeling functions.

    Hoffman, Huxley K / Fernandez, Melissa V / Groves, Nicholas S / Freed, Eric O / van Engelenburg, Schuyler B

    The Journal of biological chemistry

    2019  Volume 294, Issue 44, Page(s) 16266–16281

    Abstract: The endosomal sorting complexes required for transport (ESCRT) machinery drives membrane scission for diverse cellular functions that require budding away from the cytosol, including cell division and transmembrane receptor trafficking and degradation. ... ...

    Abstract The endosomal sorting complexes required for transport (ESCRT) machinery drives membrane scission for diverse cellular functions that require budding away from the cytosol, including cell division and transmembrane receptor trafficking and degradation. The ESCRT machinery is also hijacked by retroviruses, such as HIV-1, to release virions from infected cells. The crucial roles of the ESCRTs in cellular physiology and viral disease make it imperative to understand the membrane scission mechanism. Current methodological limitations, namely artifacts caused by overexpression of ESCRT subunits, obstruct our understanding of the spatiotemporal organization of the endogenous human ESCRT machinery. Here, we used CRISPR/Cas9-mediated knock-in to tag the critical ESCRT-I component tumor susceptibility 101 (Tsg101) with GFP at its native locus in two widely used human cell types, HeLa epithelial cells and Jurkat T cells. We validated this approach by assessing the function of these knock-in cell lines in cytokinesis, receptor degradation, and virus budding. Using this probe, we measured the incorporation of endogenous Tsg101 in released HIV-1 particles, supporting the notion that the ESCRT machinery initiates virus abscission by scaffolding early-acting ESCRT-I within the head of the budding virus. We anticipate that these validated cell lines will be a valuable tool for interrogating dynamics of the native human ESCRT machinery.
    MeSH term(s) CRISPR-Cas Systems ; Cytokinesis/physiology ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Endosomal Sorting Complexes Required for Transport/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism ; Genomics/methods ; HIV-1/metabolism ; HeLa Cells ; Humans ; Jurkat Cells ; Protein Transport ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Virion/metabolism ; Virus Release
    Chemical Substances DNA-Binding Proteins ; Endosomal Sorting Complexes Required for Transport ; Transcription Factors ; Tsg101 protein
    Language English
    Publishing date 2019-09-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA119.009372
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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  8. Article ; Online: Three-Dimensional Reflectance Traction Microscopy.

    Kim, Jihan / Jones, Christopher A R / Groves, Nicholas Scott / Sun, Bo

    PloS one

    2016  Volume 11, Issue 6, Page(s) e0156797

    Abstract: Cells in three-dimensional (3D) environments exhibit very different biochemical and biophysical phenotypes compared to the behavior of cells in two-dimensional (2D) environments. As an important biomechanical measurement, 2D traction force microscopy can ...

    Abstract Cells in three-dimensional (3D) environments exhibit very different biochemical and biophysical phenotypes compared to the behavior of cells in two-dimensional (2D) environments. As an important biomechanical measurement, 2D traction force microscopy can not be directly extended into 3D cases. In order to quantitatively characterize the contraction field, we have developed 3D reflectance traction microscopy which combines confocal reflection imaging and partial volume correlation postprocessing. We have measured the deformation field of collagen gel under controlled mechanical stress. We have also characterized the deformation field generated by invasive breast cancer cells of different morphologies in 3D collagen matrix. In contrast to employ dispersed tracing particles or fluorescently-tagged matrix proteins, our methods provide a label-free, computationally effective strategy to study the cell mechanics in native 3D extracellular matrix.
    MeSH term(s) Animals ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Cell Shape ; Collagen/metabolism ; Extracellular Matrix/metabolism ; Female ; Gels ; Humans ; Imaging, Three-Dimensional/methods ; Microscopy/methods ; Microscopy, Confocal/methods ; Porosity ; Rats ; Reproducibility of Results ; Stress, Mechanical
    Chemical Substances Gels ; Collagen (9007-34-5)
    Language English
    Publishing date 2016-06-15
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0156797
    Database MEDical Literature Analysis and Retrieval System OnLINE

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