EMD-20347
Polyclonal serum of rabbit A1 post 6th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+, class 2
EMD-20347
Single-particle24.0 Å
Deposition: 25/06/2019Map released: 20/11/2019
Last modified: 01/04/2020
Sample Organism:
Homo sapiens
Sample: Polyclonal serum of rabbit A1 post 6th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+, class 2
Deposition Authors: Turner HL, Andrew AB
Sample: Polyclonal serum of rabbit A1 post 6th immunization in complex with heterologous Env trimer 45_01dG5 NFL TD 2CC+, class 2
Deposition Authors: Turner HL, Andrew AB
Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.
Dubrovskaya V,
Tran K,
Ozorowski G,
Guenaga J,
Wilson R,
Bale S,
Cottrell CA 
,
Turner HL,
Seabright G,
O'Dell S,
Torres JL ,
Yang L,
Feng Y,
Leaman DP,
Vazquez Bernat N,
Liban T,
Louder M,
McKee K,
Bailer RT,
Movsesyan A,
Doria-Rose NA,
Pancera M,
Karlsson Hedestam GB,
Zwick MB,
Crispin M ,
Mascola JR,
Ward AB,
Wyatt RT
(2019) Immunity , 51 , 915 - 929.e7
,
Turner HL,
Seabright G,
O'Dell S,
Torres JL ,
Yang L,
Feng Y,
Leaman DP,
Vazquez Bernat N,
Liban T,
Louder M,
McKee K,
Bailer RT,
Movsesyan A,
Doria-Rose NA,
Pancera M,
Karlsson Hedestam GB,
Zwick MB,
Crispin M ,
Mascola JR,
Ward AB,
Wyatt RT
(2019) Immunity , 51 , 915 - 929.e7
Abstract:
The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.
The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.