Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions.

TitleGermline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions.
Publication TypeJournal Article
Year of Publication2023
AuthorsCaniels 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
JournalCell Rep Med
Volume4
Issue4
Pagination101003
Date Published2023 Apr 18
ISSN2666-3791
KeywordsAnimals, 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.

DOI10.1016/j.xcrm.2023.101003
Alternate JournalCell Rep Med
PubMed ID37044090
PubMed Central IDPMC10140475
Grant ListUM1 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

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