Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core

Abstract

VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1–3 in the presence and absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.

Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan

“…The lineage then affinity matures into two main branches, where one remains dependent on the N276 glycan for binding and the other gaining affinity for the CD4bs epitope in the absence of the N276 glycan. Together with the recent finding that VRC01 inferred GL Ab interacted with the N276-glycan of 426c gp120 core lacking the V1-V2-V3 loops (Borst et al., 2018), these data suggest an alternative vaccine design strategy where the N276-glycan is present on the germline-targeting immunogens at the initial priming stages to select for early intermediates with glycan-binding properties, which could be subsequently boosted with immunogens to affinity mature intermediate precursors to relinquish dependency on the glycan and acquire higher affinity for the CD4bs epitope. A similar strategy was suggested for V2-apex directed Abs upon observation that varying affinities for particular glycoforms were associated with the elicitation of the PCT64 lineage (Landais et al., 2017, Rantalainen et al., 2018).…”

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

“…Computational analysis of viral strains containing residue T444 gp120 (37% of 3260 Env sequences in Antibody Database) (West et al., 2013) showed that 78% of the T444 gp120 -containing sequences included an asparagine at position 442 gp120 to create a 442 gp120 PNGS. To determine whether a glycan at position N442 gp120 would disrupt SF12 binding, we modeled coordinates for the N442 gp120 glycan from the clade C 426c DS-SOSIP structure (Borst et al., 2018) after superposing the PDB 6MYY gp120 onto the gp120 of our Env trimer structure and adding in the N442 gp120 glycan. In the conformation observed on the 426c Env structure, the N442 gp120 glycan would clash with SF12 heavy chain CDRH1 and FWR3 components, sterically hindering access to its epitope (Figure 5D).…”

Structural basis of broad HIV neutralization by a vaccine-induced cow antibody

“…on November 4, 2020 http://advances.sciencemag.org/ Downloaded from to the CD4bs by immunization (35,36). The long, narrow cow CDR H3 helps navigate past the glycans to contact the underlying CD4bs.…”