title: Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign.
abstract: HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign.
authors.affiliation: International AIDS Vaccine Initiative Neutralizing Antibody Center, Departments of Integrative Structural and Computational Biology and Immunology and Microbial Science, and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Karen
authors.initials: K
authors.lastname: Tran
authors.forename: Christian
authors.initials: C
authors.lastname: Poulsen
authors.forename: Javier
authors.initials: J
authors.lastname: Guenaga
authors.forename: Natalia
authors.initials: N
authors.lastname: de Val
authors.forename: Natalia
authors.initials: N
authors.lastname: de Val Alda
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.forename: Christopher
authors.initials: C
authors.lastname: Sundling
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Stanfield
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
mesh_terms: D016915:AIDS Vaccines / Q000096:biosynthesis / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D003460:Crystallization; D015195:Drug Design; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta / Q000276:immunology*; D008857:Microscopy, Interference; D008958:Models, Molecular; D009500:Neutralization Tests; D011487:Protein Conformation; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D007140:Immunoglobulin Fab Fragments; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: NHP; mode of recognition; neutralizing antibodies