Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques

Cell. 2024 Jan 4;187(1):79-94.e24. doi: 10.1016/j.cell.2023.12.002.


The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.

Keywords: CD4 binding site; CD4-mimetic antibody; EM polyclonal epitope mapping; EMPEM; HIV vaccine; broadly neutralizing antibodies; cryo-EM; cryo-electron microscopy; rhesus macaques.

Publication types

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

MeSH terms

  • AIDS Vaccines* / immunology
  • Animals
  • Broadly Neutralizing Antibodies
  • CD4 Antigens
  • Cell Adhesion Molecules
  • HIV-1* / physiology
  • Humans
  • Macaca


  • Broadly Neutralizing Antibodies
  • CD4 Antigens
  • Cell Adhesion Molecules
  • AIDS Vaccines