B cell recognition of the conserved HIV-1 co-receptor binding site is altered by endogenous primate CD4

PLoS Pathog. 2008 Oct 3;4(10):e1000171. doi: 10.1371/journal.ppat.1000171.


The surface HIV-1 exterior envelope glycoprotein, gp120, binds to CD4 on the target cell surface to induce the co-receptor binding site on gp120 as the initial step in the entry process. The binding site is comprised of a highly conserved region on the gp120 core, as well as elements of the third variable region (V3). Antibodies against the co-receptor binding site are abundantly elicited during natural infection of humans, but the mechanism of elicitation has remained undefined. In this study, we investigate the requirements for elicitation of co-receptor binding site antibodies by inoculating rabbits, monkeys and human-CD4 transgenic (huCD4) rabbits with envelope glycoprotein (Env) trimers possessing high affinity for primate CD4. A cross-species comparison of the antibody responses showed that similar HIV-1 neutralization breadth was elicited by Env trimers in monkeys relative to wild-type (WT) rabbits. In contrast, antibodies against the co-receptor site on gp120 were elicited only in monkeys and huCD4 rabbits, but not in the WT rabbits. This was supported by the detection of high-titer co-receptor antibodies in all sera from a set derived from human volunteers inoculated with recombinant gp120. These findings strongly suggest that complexes between Env and (high-affinity) primate CD4 formed in vivo are responsible for the elicitation of the co-receptor-site-directed antibodies. They also imply that the naïve B cell receptor repertoire does not recognize the gp120 co-receptor site in the absence of CD4 and illustrate that conformational stabilization, imparted by primary receptor interaction, can alter the immunogenicity of a type 1 viral membrane protein.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Viral / genetics
  • Antibodies, Viral / immunology*
  • B-Lymphocytes / immunology*
  • Binding Sites, Antibody / genetics
  • Binding Sites, Antibody / immunology
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology*
  • Cell Line
  • Female
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / immunology*
  • HIV Infections / genetics
  • HIV Infections / immunology*
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Humans
  • Macaca fascicularis
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology
  • Rabbits
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology
  • Species Specificity
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology


  • Antibodies, Viral
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Multiprotein Complexes
  • Receptors, Antigen, B-Cell
  • env Gene Products, Human Immunodeficiency Virus
  • gp120 protein, Human immunodeficiency virus 1