Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design

Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1-Env V1V2 arise in multiple donors. However, atomic-level interactions had only been determined with antibodies from a single donor, making commonalities in recognition uncertain. Here we report the co-crystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third. These V1V2-directed bNAbs utilized strand-strand interactions between a protruding antibody loop and a V1V2 strand, but differed in their N-glycan recognition. Ontogeny analysis indicated protruding loops to develop early, with glycan interactions maturing over time. Altogether, the multidonor information suggested V1V2-directed bNAbs to form an ‘extended class’, for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…V1V2-glycan bnAbs, such as the PG9, CH01, PGT145 and CAP256-VRC26 lineages, are characterized by anionic, often tyrosine-sulfated, long and protruding CDR H3s that penetrate HIV envelope glycans and recognize a discontinuous epitope at the apex of the HIV-1 spike (14, 15,19,22,25,51–54). Crystal structures in complex with a scaffolded V1V2 domain were solved for PG9, PG16 (in the PG9 lineage) (51, 52), and CH03, CH04 (in the CH01 lineage) (55). V1V2 glycan bnAbs recognize a discontinuous epitope around an N-linked glycan at position 160, with a preference for short high mannose glycans, e.g.…”

“…Man 5 GlcNac 2 (52). V1V2 bnAb interactions with various glycans and direct strand-strand contact between the extended CDR H3 and the C strand of the V1V2 domain are common traits among individual V1V2 bnAbs (51, 52, 55, 56). For immunogen design, despite V1V2 glycan bnAb preference for binding to a quaternary epitope, PG9, PG16 and CH01 bnAbs, as well as the CH01 lineage unmutated common ancestor (UCA), can also bind a minor subset of monomeric gp120 Envs (15, 57) and minimal Env forms (58).…”

“…While such immunogens are designed for the UCA and intermediate antibodies of one particular bnAb lineage, they hold promise for inducing bnAb lineages in multiple individuals because of the remarkable conserved usage of V H and V L genes of bnAbs and the restricted nature of antibody motifs for many bnAb types, particularly for the gp41 membrane proximal region (89), the CD4 binding site (42) and the V1V2-glycan site (15, 41, 55, 56). To mimic the progression of maturation of bnAb lineages, each Env should engage a bnAb precursor with affinity sufficient to trigger the B cell but with low binding affinity to allow for affinity maturation to the next stage of bnAb development.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…This results at least in part from bNAbs critically interacting with the same structural motif in the targeted region. The two clearest examples of this phenomenon (Figure 2B) are the V2g bNAbs (eg, CAP256), which generally target the N‐linked glycan at Env position 160, eg, Gorman et al 62,. and the V3g bNAbs (eg, PGT128) which generally target an N‐linked glycan at position 332, eg, Kong et al 63…”

“…The contact regions are shown on the crystal structure of a subtype G Env SOSIP trimer60 ( PDB : 5 FYJ ), colored according to the bNA b epitope, with different colors for overlapping contact sites of multiple bNA bs. For calculations of bNA b contact regions, crystal structures for antibodies CH 235.1268 ( PDB :5F96), PGT 12889 ( PDB : 5C7K) and 10E890 ( PDB :4G6F), and a structural model for CAP 256‐ VRC 26.0962 were used. A generous cutoff of 8.5 Å between heavy atoms of antibody and Env was used to define contacts, so as to capture the full region where Env amino acid substitutions might directly impact binding.…”