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Principal Investigator: Bing Chen
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $784,041
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Structural insights from our recent work provide a strong scientific premise for exploring the membrane-related
components of HIV-1 envelope glycoprotein (Env), including the membrane proximal external region (MPER),
the transmembrane domain (TMD) and the cytoplasmic tail (CT), for vaccine development. Our data indicate
that all these regions influence the stability and antigenicity of the Env ectodomain. Major broadly neutralizing
antibody (bnAb) epitopes on HIV-1 Env include CD4 binding site, V1V2-glycan, V3-glycan, the fusion
peptide/gp120-gp41 interface and the MPER. The optimal presentation of these epitopes, critical for their
antigenicity and immunogenicity, depends on the Env trimer organization and conformation. Recently, the fusion
peptide-based immunogens have induced robust cross-clade neutralizing responses in animal models,
suggesting that bnAbs may be elicited by vaccination. In this research project, our central hypothesis is that
rationally designed HIV-1 Env immunogens in different conformations with various degrees of bnAb epitope
exposure induce different B cell responses, which may lead to production of diverse bnAbs in animal models
and to new strategies for HIV-1 vaccine immunogen design. The research team is formed by a group of
outstanding investigators with diverse yet complementary expertise to carry out the proposed studies. This group
has extensive experience in protein engineering, production and characterization, in B cell biology and
vaccinology in animal models, and in detailed analysis of vaccine-elicited antibody responses. The group
members have an extensive history of working together on HIV-1 and SARS-CoV-2 related projects. The team
will capitalize on the newly determined structures of the membrane-related components of HIV-1 Env to develop
two innovative immunogen-design strategies: (1) soluble Env trimer immunogens and (2) membrane-bound
intact Env trimer immunogens. We propose two Specific Aims to test the hypothesis: Aim 1. We will design,
characterize and produce Env-based immunogens in both the protein and mRNA forms and perform structural
studies of Env-based immunogens and their complexes with antibodies. Aim 2. We will evaluate immunogenicity
of novel Env-based protein immunogens and mRNA vaccines in VelocImmune human antibody mice.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cell Activation><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Binding Sites><Blood Serum><COVID-19 virus><COVID19 virus><Cellular biology><CoV-2><CoV2><Combining Site><Complex><Cytoplasmic Domain><Cytoplasmic Tail><Data><Epitopes><Evolution><Glycans><Glycoproteins><Goals><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><HTLV-III gp120><History><Hu-mABs><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Ig Genes><Immune response><Immunoglobulin Genes><Immunological response><Investigators><Laboratory mice><Length><Membrane><Messenger RNA><Mice><Mice Mammals><Modern Man><Modification><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Peptides><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Polysaccharides><Production><Property><Protein Engineering><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RNA vaccine><RNA-based vaccine><Reactive Site><Recombinants><Recording of previous events><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Structure><Surface><TM Domain><Testing><Transmembrane Domain><Transmembrane Region><Vaccination><Vaccines><Virion><Virus Particle><Work><Wuhan coronavirus><activated B cells><cell biology><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 virus><coronavirus disease-19 virus><design><designing><develop a vaccine><develop vaccines><development of a vaccine><experience><genetic protein engineering><gp120><gp120 ENV Glycoprotein><gp120(HIV)><hCoV19><histories><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immune system response><immunogen><immunogenicity><immunoresponse><innovate><innovation><innovative><insight><mRNA><mRNA vaccine><mRNA-based vaccine><member><membrane structure><model of animal><nCoV2><neutralizing antibody><next generation><novel><pharmaceutical><programs><protein design><rational design><response><vaccine development><vaccinology>