Title | Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Caniels TG, Medina-Ramírez M, Zhang J, Sarkar A, Kumar S, LaBranche A, Derking R, Allen JD, Snitselaar JL, Capella-Pujol J, Sánchez IDel Moral, Yasmeen A, Diaz M, Aldon Y, Bijl TPL, Venkatayogi S, Beem JSMartin, Newman A, Jiang C, Lee W-H, Pater M, Burger JA, van Breemen MJ, de Taeye SW, Rantalainen K, LaBranche C, Saunders KO, Montefiori D, Ozorowski G, Ward AB, Crispin M, Moore JP, Klasse PJohan, Haynes BF, Wilson IA, Wiehe K, Verkoczy L, Sanders RW |
Journal | Cell Rep Med |
Volume | 4 |
Issue | 4 |
Pagination | 101003 |
Date Published | 2023 Apr 18 |
ISSN | 2666-3791 |
Keywords | Animals, Antibodies, Neutralizing, Broadly Neutralizing Antibodies, HIV Antibodies, HIV Seropositivity, HIV-1, Mice, Vaccination |
Abstract | Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions. |
DOI | 10.1016/j.xcrm.2023.101003 |
Alternate Journal | Cell Rep Med |
PubMed ID | 37044090 |
PubMed Central ID | PMC10140475 |
Grant List | UM1 AI144462 / AI / NIAID NIH HHS / United States UM1 AI100645 / AI / NIAID NIH HHS / United States HHSN272201800004C / AI / NIAID NIH HHS / United States R01 AI087202 / AI / NIAID NIH HHS / United States R01 AI036082 / AI / NIAID NIH HHS / United States P30 GM138396 / GM / NIGMS NIH HHS / United States P01 AI110657 / AI / NIAID NIH HHS / United States UM1 AI144371 / AI / NIAID NIH HHS / United States |
Submitted by ljc4002 on August 21, 2025 - 3:01pm