Trimeric HIV Env provides epitope occlusion mediated by hypervariable loops. 2014

Carlos G Moscoso, and Li Xing, and Jinwen Hui, and Jeffrey Hu, and Mohammad Baikoghli Kalkhoran, and Onur M Yenigun, and Yide Sun, and Lassi Paavolainen, and Loïc Martin, and Anders Vahlne, and Carlo Zambonelli, and Susan W Barnett, and Indresh K Srivastava, and R Holland Cheng
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.

Hypervariable loops of HIV-1 Env protein gp120 are speculated to play roles in the conformational transition of Env to the receptor binding-induced metastable state. Structural analysis of full-length Env-based immunogens, containing the entire V2 loop, displayed tighter association between gp120 subunits, resulting in a smaller trimeric diameter than constructs lacking V2. A prominent basal quaternary location of V2 and V3' that challenges previous reports would facilitate gp41-independent gp120-gp120 interactions and suggests a quaternary mechanism of epitope occlusion facilitated by hypervariable loops. Deletion of V2 resulted in dramatic exposure of basal, membrane-proximal gp41 epitopes, consistent with its predicted basal location. The structural features of HIV-1 Env characterized here provide grounds for a paradigm shift in loop exposure and epitope occlusion, while providing substantive rationale for epitope display required for elicitation of broadly neutralizing antibodies, as well as substantiating previous pertinent literature disregarded in recent reports.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000939 Epitopes Sites on an antigen that interact with specific antibodies. Antigenic Determinant,Antigenic Determinants,Antigenic Specificity,Epitope,Determinant, Antigenic,Determinants, Antigenic,Specificity, Antigenic
D015699 HIV Envelope Protein gp120 External envelope protein of the human immunodeficiency virus which is encoded by the HIV env gene. It has a molecular weight of 120 kDa and contains numerous glycosylation sites. Gp120 binds to cells expressing CD4 cell-surface antigens, most notably T4-lymphocytes and monocytes/macrophages. Gp120 has been shown to interfere with the normal function of CD4 and is at least partly responsible for the cytopathic effect of HIV. Envelope Glycoprotein gp120, HIV,HTLV-III gp120,env Protein gp120, HIV,gp120(HIV),HIV Envelope Glycoprotein gp120,gp120 Envelope Glycoprotein, HIV,HTLV III gp120,gp120, HTLV-III
D015700 HIV Envelope Protein gp41 Transmembrane envelope protein of the HUMAN IMMUNODEFICIENCY VIRUS which is encoded by the HIV env gene. It has a molecular weight of 41,000 and is glycosylated. The N-terminal part of gp41 is thought to be involved in CELL FUSION with the CD4 ANTIGENS of T4 LYMPHOCYTES, leading to syncytial formation. Gp41 is one of the most common HIV antigens detected by IMMUNOBLOTTING. Envelope Protein gp41, HIV,HIV Transmembrane Protein gp41,HTLV-III gp41,env Protein gp41, HIV,gp41(HIV),gp41 Envelope Protein, HIV
D015704 CD4 Antigens 55-kDa antigens found on HELPER-INDUCER T-LYMPHOCYTES and on a variety of other immune cell types. They are members of the immunoglobulin supergene family and are implicated as associative recognition elements in MAJOR HISTOCOMPATIBILITY COMPLEX class II-restricted immune responses. On T-lymphocytes they define the helper/inducer subset. T4 antigens also serve as INTERLEUKIN-15 receptors and bind to the HIV receptors, binding directly to the HIV ENVELOPE PROTEIN GP120. Antigens, CD4,CD4 Molecule,CD4 Receptor,CD4 Receptors,Receptors, CD4,T4 Antigens, T-Cell,CD4 Antigen,Receptors, Surface CD4,Surface CD4 Receptor,Antigen, CD4,Antigens, T-Cell T4,CD4 Receptor, Surface,CD4 Receptors, Surface,Receptor, CD4,Surface CD4 Receptors,T-Cell T4 Antigens,T4 Antigens, T Cell
D017384 Sequence Deletion Deletion of sequences of nucleic acids from the genetic material of an individual. Deletion Mutation,Deletion Mutations,Deletion, Sequence,Deletions, Sequence,Mutation, Deletion,Mutations, Deletion,Sequence Deletions

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