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  1. Article ; Online: Assessing immunogenicity barriers of the HIV-1 envelope trimer.

    Maliqi, Liridona / Friedrich, Nikolas / Glögl, Matthias / Schmutz, Stefan / Schmidt, Daniel / Rusert, Peter / Schanz, Merle / Zaheri, Maryam / Pasin, Chloé / Niklaus, Cyrille / Foulkes, Caio / Reinberg, Thomas / Dreier, Birgit / Abela, Irene / Peterhoff, David / Hauser, Alexandra / Kouyos, Roger D / Günthard, Huldrych F / van Gils, Marit J /
    Sanders, Rogier W / Wagner, Ralf / Plückthun, Andreas / Trkola, Alexandra

    NPJ vaccines

    2023  Volume 8, Issue 1, Page(s) 148

    Abstract: Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, ...

    Abstract Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.
    Language English
    Publishing date 2023-09-30
    Publishing country England
    Document type Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-023-00746-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.

    Glögl, Matthias / Friedrich, Nikolas / Cerutti, Gabriele / Lemmin, Thomas / Kwon, Young D / Gorman, Jason / Maliqi, Liridona / Mittl, Peer R E / Hesselman, Maria C / Schmidt, Daniel / Weber, Jacqueline / Foulkes, Caio / Dingens, Adam S / Bylund, Tatsiana / Olia, Adam S / Verardi, Raffaello / Reinberg, Thomas / Baumann, Nicolas S / Rusert, Peter /
    Dreier, Birgit / Shapiro, Lawrence / Kwong, Peter D / Plückthun, Andreas / Trkola, Alexandra

    Nature structural & molecular biology

    2023  Volume 30, Issue 9, Page(s) 1323–1336

    Abstract: The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly ... ...

    Abstract The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.
    MeSH term(s) Humans ; HIV-1 ; Amino Acids ; Antibodies ; Binding Sites ; Molecular Conformation
    Chemical Substances Amino Acids ; Antibodies
    Language English
    Publishing date 2023-08-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-023-01062-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization.

    Friedrich, Nikolas / Stiegeler, Emanuel / Glögl, Matthias / Lemmin, Thomas / Hansen, Simon / Kadelka, Claus / Wu, Yufan / Ernst, Patrick / Maliqi, Liridona / Foulkes, Caio / Morin, Mylène / Eroglu, Mustafa / Liechti, Thomas / Ivan, Branislav / Reinberg, Thomas / Schaefer, Jonas V / Karakus, Umut / Ursprung, Stephan / Mann, Axel /
    Rusert, Peter / Kouyos, Roger D / Robinson, John A / Günthard, Huldrych F / Plückthun, Andreas / Trkola, Alexandra

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 6705

    Abstract: The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3- ... ...

    Abstract The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of V3-base bnAbs. While most bnAbs target prefusion Env, V3-crown bnDs bind open Env conformations triggered by CD4 engagement. BnDs achieve breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3. We further show that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth. Our results indicate a role of V3-crown responses and its conformational preferences in bnAb development to be considered in preventive and therapeutic approaches.
    MeSH term(s) Antibodies, Neutralizing/immunology ; Antibodies, Neutralizing/metabolism ; Cell Line, Tumor ; Epitopes/genetics ; Epitopes/immunology ; Epitopes/metabolism ; HEK293 Cells ; HIV Antibodies/immunology ; HIV Antibodies/metabolism ; HIV-1/genetics ; HIV-1/immunology ; HIV-1/metabolism ; Humans ; Immunoglobulin G/immunology ; Immunoglobulin G/metabolism ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Protein Conformation ; env Gene Products, Human Immunodeficiency Virus/chemistry ; env Gene Products, Human Immunodeficiency Virus/genetics ; env Gene Products, Human Immunodeficiency Virus/immunology
    Chemical Substances Antibodies, Neutralizing ; Epitopes ; HIV Antibodies ; Immunoglobulin G ; env Gene Products, Human Immunodeficiency Virus
    Language English
    Publishing date 2021-11-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-27075-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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