Document text
Principal Investigator: Michael R. Farzan
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $891,681
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
What is the shortest path from the human antibody repertoire to sera that protects from an HIV-1 challenge?
We propose here that this pathway starts from B-cell receptors (BCRs) with long, tyrosine-sulfated heavy-
chain CDR3s (HCDR3s) encoded by D3-family of diversity (D) chain segments. This path ends with broadly
neutralizing antibodies (bnAbs) targeting the V2-glycan or ‘apex’ epitope of the HIV-1 envelope glycoprotein
(Env). That is, the most direct way to prevent many HIV-1 transmission events through conventional
vaccination is to induce a defined subset of circulating HCDR3s to bind the Env apex.
This hypothesis is supported by several observations: (1) Apex bnAbs do not require extensive or rare
hypermutations. (2) Neutralization by key apex bnAbs, notably those of the PG9/PG16 and VRC26 families,
is largely mediated by their HCDR3 regions. (3) These key bnAbs bind their distinct apex epitopes through
HCDR3 encoded by long (>24 amino-acid), tyrosine-sulfated D3-family diversity (D) segments, specifically
via ‘YYDF’ motifs encoded by the D3-3 segment. (4) BCR bearing HCDR3 with these properties are present
in humans at a frequency of 1 in 2000, far more frequently than other proposed bnAb precursors. Further, (5)
when we introduced with CRISPR/Cas12a only the HCDR3s of PG16 and VRC26.25 into a diverse population
of murine BCRs, B cells encoding these chimeric BCRs affinity matured and generated potent neutralizing
sera in recipient mice immunized with trimeric Env (SOSIP-TM) antigens. (6) When we similarly edited murine
B cells to express the HCDR3 of the VRC26-family unmutated common ancestor (UCA), they similarly affinity
matured and generated potent neutralizing sera in recipient mice. Finally, as we show here, (7) SOSIP-TM
proteins can be modified to bind common D3-3-encoded HCDR3 from HIV-negative persons while continuing
to engage mature apex bnAbs. In summary, potential apex-bnAb precursors with long D3-family HCDR3 are
common, these precursors can bind SOSIP-TM variants with unmodified apex epitopes, and they can affinity
mature in response to SOSIP-TM antigens in wild-type mice engrafted with human HCDR3-edited B cells.
Our goals then are to refine our definition of accessible apex bnAb precursors found frequently in uninfected
persons, and to identify sets of SOSIP-TM antigens that affinity mature these precursors so that they generate
polyclonal sera and monoclonal bnAbs that protect from multiple HIV-1 isolates. To do so, we will use our
useful variant of mammalian display technology (Yin et al., PNAS 2021) and our novel mouse models for
vaccine evaluation (He, Ou et al., Immunity 2023; Yin et al., Nat Biomed Eng, 2024). These models rely on
our ability to introduce human HCDR3, or whole human antibodies, directly into their appropriate VDJ (VJ)-
recombined loci of murine B cells, and then affinity mature the resulting BCR chimeras in vivo.
Collectively, these studies will determine the best antigens and vaccination strategies to generate apex bnAbs
in uninfected persons. In doing so, they will complement parallel efforts to elicit other classes of bnAbs.
Terms: <AIDS Virus><Ab-mediated immunity><Ab-mediated protection><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Amino Acids><Antibodies><Antibody Repertoire><Antibody Response><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigenic Determinants><Antigens><Apical><B Cell Proliferation><B blood cells><B cell><B cell receptor><B cell repertoire><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><CRISPR><CRISPR/Cas system><Characteristics><Chimera><Chimera organism><Clustered Regularly Interspaced Short Palindromic Repeats><Complement><Complement Proteins><Complementarity Determining Regions><Complimentarity Determining Region><Consensus Sequence><Cryo-electron Microscopy><Cryoelectron Microscopy><Development><Electron Cryomicroscopy><Engraftment><Epitopes><Event><Family><Frequencies><Genes><Glycans><Glycoproteins><Goals><HIV><HIV Seronegativities><HIV Seronegativity><HIV negative><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><HTLV-III Seronegativities><HTLV-III Seronegativity><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Humoral Immunities><Hypervariable Loop><Hypervariable Regions><Ig Somatic Hypermutation><Immunity><Immunization><Immunize><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunoglobulin Hypervariable Region><Immunoglobulin Somatic Hypermutation><LAV-HTLV-III><Laboratories><Libraries><Light><Lymphadenopathy-Associated Virus><Macaca><Macaque><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Pathway interactions><Persons><Photoradiation><Physiologic><Physiological><Polysaccharides><Population Heterogeneity><Process><Property><Proteins><Rodent><Rodentia><Rodents Mammals><Series><Structure><Surface><TM Domain><Technology><Testing><Transgenic Mice><Transmembrane Domain><Transmembrane Region><Transmission><Vaccination><Vaccines><Variant><Variation><Virus><Virus-HIV><Wild Type Mouse><Writing><Yin><aminoacid><antibody-based immunity><antibody-mediated immunity><antigen binding><antigen bound><chimeras><complementation><cryo-EM><cryoEM><cryogenic electron microscopy><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><developmental><diverse populations><evaluate vaccines><heterogeneous population><human model><immunization strategy><immunogen><immunogenic><immunogenicity><in vivo><insight><lipid based nanoparticle><lipid nanoparticle><mRNA delivery><messenger RNA delivery><model of human><mouse model><murine model><neutralizing antibody><novel><pandemic><pandemic disease><pathway><population diversity><prevent><preventing><progenitor><rational design><response><somatic hypermutation><sulfotyrosine><transmission process><tyrosine O-sulfate><tyrosine sulfate><vaccination strategy><vaccine evaluation><vaccine screening><vaccine strategy><vaccine testing><wildtype mouse>