Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1

J Virol. 2003 Oct;77(19):10557-65. doi: 10.1128/jvi.77.19.10557-10565.2003.


Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Binding Sites
  • CD4 Antigens / immunology*
  • CD4 Antigens / metabolism
  • Epitopes
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fragments / immunology
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Neutralization Tests
  • Receptors, CCR5 / immunology
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / immunology
  • Receptors, CXCR4 / metabolism


  • Antibodies, Monoclonal
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Fragments
  • Immunoglobulin G
  • Receptors, CCR5
  • Receptors, CXCR4
  • immunoglobulin Fv