# An Env apex-focused HIV-1 vaccine strategy > **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $891,681 ## Abstract 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 vaccina... ## Key facts - **NIH application ID:** 11009104 - **Project number:** 1R01AI186793-01 - **Recipient organization:** BOSTON CHILDREN'S HOSPITAL - **Principal Investigator:** Michael R. Farzan - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $891,681 - **Award type:** 1 - **Project period:** 2024-07-24 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/11009104 ## Citation > US National Institutes of Health, RePORTER application 11009104, An Env apex-focused HIV-1 vaccine strategy (1R01AI186793-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11009104. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*