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Principal Investigator: Bing Chen
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2023
Award: $531,000
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Membrane fusion, mediated by HIV-1 envelope glycoprotein [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3],
is the first critical step for the virus to enter host cells and establish infection. A mature Env spike contains
three copies each of noncovalently-associated receptor-binding subunit gp120 and fusion subunit gp41. A
general picture of viral membrane fusion has emerged from extensive biochemical and structural studies.
Sequential binding of gp120 to the primary receptor CD4 and a coreceptor leads to large, irreversible structural
rearrangements in gp41, which drive the membrane fusion process. Despite tremendous progress in our
understanding of the structure of HIV-1 Env over the last two decades, largely based on studies of its soluble
fragments, we still lack an atomic picture of the full-length Env in a membrane environment. In a series of
recent studies, we have determined the structures of the transmembrane domain, membrane proximal external
region, as well as a portion of the cytoplasmic tail of HIV-1 Env in bicelles that mimic lipid bilayers by NMR.
Unexpectedly, we find that these regions all form well-ordered trimeric clusters in the presence of a lipid bilayer
and that disruption of any of them reduces membrane fusion efficiency and alters the antigenic structure of the
entire Env, suggesting that they play critical structural and functional roles. These new findings provide a
strong scientific premise to determine the structure of the full-length HIV-1 Env reconstituted in lipid
nanodiscs by cryo-electron microscopy (cryoEM). We hypothesize that the transmembrane and membrane-
proximal regions of HIV-1 Env all adopt defined oligomeric structures that are critical for the stability,
function and antigenicity of the full-length protein in membrane. We will capitalize on the recent advances
in cryoEM and nanodisc technology and plan to determine structures of the full-length Env proteins,
reconstituted in lipid bilayers, both alone or in complex with the matrix protein. Our goal is to visualize novel
structural features of the intact Env proteins in the context of membrane, to gain a full understanding of their
structure-function and to facilitate Env-based immunogen design for vaccine development. We will purse the
following specific aims: 1) we will determine the structure of a full-length HIV-1 Env in the context of
membrane, 2) we will determine the structural basis for antigenic differences of the intact Env in membrane
among HIV-1 isolates with different antibody sensitivity, and 3) we will determine the structure of a full-length
HIV-1 Env in complex with matrix protein.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adopted><Antibodies><Antigens><Binding><Biochemical><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CD4 Antigens><CD4 Molecule><CD4 Protein><CD4 Receptors><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><CXC-R4><CXCR-4><CXCR4><CXCR4 gene><Cell Body><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chemokine Receptor Gene><Complex><Core protein p17, Human immunodeficiency virus type 1><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasmic Domain><Cytoplasmic Protein><Cytoplasmic Tail><D2S201E><Electron Cryomicroscopy><Envelope Protein><Environment><FB22><Genetic><Genetic Diversity><Genetic Variation><Glycoproteins><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV GGP p17><HIV env Protein gp120><HIV gag protein p17><HIV p17 antigen><HIV-1><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV-1 MA protein><HIV-1 matrix protein><HIV-1 p17 matrix protein><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><HM89><HSY3RR><HTLV-III gp120><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Infection><LAP3><LAV-HTLV-III><LCR1><LESTR><Lead><Length><Lipid Bilayers><Lipids><Lymphadenopathy-Associated Virus><Mediating><Membrane><Membrane Fusion><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><NPY3R><NPYR><NPYRL><NPYY3R><OKT4 antigen><Pb element><Play><Probability><Process><Proteins><Protocol><Protocols documentation><Receptor Protein><Reporting><Resistance><Resolution><Retroviral Antigen gag Protein><Role><Sampling><Series><Structure><Surface CD4 Receptors><Surface Proteins><T4 molecule><TM Domain><Technology><Transmembrane Domain><Transmembrane Region><Vaccine Design><Variant><Variation><Viral><Viral gag Proteins><Virus><Virus-HIV><Visualization><chemokine receptor><conformation><conformational><conformational state><conformationally><conformations><cryo-EM><cryoEM><cryogenic electron microscopy><develop a vaccine><develop vaccines><development of a vaccine><env Antigens><env Gene Products><env Polyproteins><env Protein><gag Antigens><gag Gene Products><gag Polyproteins><gag Protein><gp120><gp120 ENV Glycoprotein><gp120(HIV)><gp160><group specific antigen><heavy metal Pb><heavy metal lead><helper T lymphocyte marker><immunogen><lipid bilayer membrane><matrix protein, Human immunodeficiency virus type 1><membrane structure><nanodisc technology><nanodisk><novel><particle><protein reconstitution><protein structure><protein structures><proteins structure><receptor><receptor binding><receptor bound><reconstitute><reconstitution><resistant><resolutions><social role><structural biology><vaccine development>