Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign

Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):E738-47. doi: 10.1073/pnas.1319512111. Epub 2014 Feb 3.


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.

Keywords: NHP; mode of recognition; neutralizing antibodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / biosynthesis
  • AIDS Vaccines / immunology*
  • Animals
  • Antibodies, Monoclonal / biosynthesis
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / biosynthesis
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Binding Sites / genetics
  • CD4 Antigens / genetics
  • CD4 Antigens / metabolism
  • Crystallization
  • Drug Design
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Fab Fragments / genetics
  • Immunoglobulin Fab Fragments / metabolism
  • Macaca mulatta / immunology*
  • Microscopy, Interference
  • Models, Molecular*
  • Neutralization Tests
  • Protein Conformation*
  • env Gene Products, Human Immunodeficiency Virus / genetics


  • AIDS Vaccines
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • CD4 Antigens
  • Immunoglobulin Fab Fragments
  • env Gene Products, Human Immunodeficiency Virus

Associated data

  • PDB/4KTD
  • PDB/4KTE