Ligand accessibility to the HIV-1 Env co-receptor binding site can occur prior to CD4 engagement and is independent of viral tier category

Virology. 2018 Jun:519:99-105. doi: 10.1016/j.virol.2018.04.002. Epub 2018 May 11.


HIV-1 virus entry into target cells requires the envelope glycoprotein (Env) to first bind the primary receptor, CD4 and subsequently the co-receptor. Antibody access to the co-receptor binding site (CoRbs) in the pre-receptor-engaged state, prior to cell attachment, remains poorly understood. Here, we have demonstrated that for tier-1 Envs, the CoRbs is directly accessible to full-length CD4-induced (CD4i) antibodies even before primary receptor engagement, indicating that on these Envs the CoRbs site is either preformed or can conformationally sample post-CD4-bound state. Tier-2 and tier-3 Envs, which are resistant to full-length CD4i antibody, are neutralized by m36.4, a lower molecular mass of CD4i-directed domain antibody. In some tier-2 and tier-3 Envs, CoRbs is accessible to m36.4 even prior to cellular attachment in an Env-specific manner independent of their tier category. These data suggest differential structural arrangements of CoRbs and varied masking of ligand access to the CoRbs in different Env isolates.

Keywords: Co-receptor-directed antibodies; Direct accessibility; HIV-1; Loop-independent.

Publication types

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

MeSH terms

  • Antibodies, Neutralizing / immunology*
  • Binding Sites
  • CD4 Antigens / immunology*
  • CD4 Antigens / metabolism
  • Epitopes / immunology
  • HIV Antibodies / immunology*
  • HIV-1 / immunology*
  • HIV-1 / metabolism
  • HIV-1 / physiology*
  • Humans
  • Ligands
  • Neutralization Tests
  • Protein Binding
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology*
  • env Gene Products, Human Immunodeficiency Virus / metabolism


  • Antibodies, Neutralizing
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • Ligands
  • env Gene Products, Human Immunodeficiency Virus