Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity

Nat Struct Mol Biol. 2010 May;17(5):608-13. doi: 10.1038/nsmb.1796. Epub 2010 Mar 31.

Abstract

Strategies to combat HIV-1 require structural knowledge of envelope proteins from viruses in HIV-1 clade C, the most rapidly spreading subtype in the world. We present a crystal structure containing a clade C gp120 envelope. The structure, a complex between gp120, the host receptor CD4 and the CD4-induced antibody 21c, reveals that the 21c epitope involves contacts with gp120, a nonself antigen, and with CD4, an autoantigen. Binding studies using wild-type and mutant CD4 show that 21c Fab binds CD4 in the absence of gp120, and that binding of 21c to clade C and HIV-2 gp120s requires the crystallographically observed 21c-CD4 interaction. Additional binding data suggest a role for the gp120 V1V2 loop in creating a high-affinity, but slow-forming, epitope for 21c after CD4 binds. These results contribute to a molecular understanding of CD4-induced antibodies and provide the first visualization to our knowledge of a potentially autoreactive antibody Fab complexed with both self and nonself antigens.

Publication types

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

MeSH terms

  • Antibodies, Viral / chemistry*
  • Antibodies, Viral / immunology*
  • CD4 Antigens / chemistry*
  • CD4 Antigens / immunology*
  • Cell Line
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Epitopes / immunology
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology*
  • HIV Infections / immunology
  • HIV-1 / chemistry
  • HIV-1 / immunology*
  • Humans
  • Models, Molecular

Substances

  • Antibodies, Viral
  • CD4 Antigens
  • Epitopes
  • HIV Envelope Protein gp120

Associated data

  • PDB/3LMJ
  • PDB/3LQA