Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region

Structure. 2016 May 3;24(5):697-709. doi: 10.1016/j.str.2016.03.005. Epub 2016 Mar 31.

Abstract

Evidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond. ID2 expresses C1-C2 epitopes in the context of CD4-triggered full-length gp120 but without any known neutralizing epitope present. Thus, ID2 represents a novel probe for the analysis and/or selective induction of antibody responses to the A32 epitope region. We also present the crystal structure of ID2 complexed with mAb A32, which defines its epitope.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Antigen-Antibody Complex / chemistry*
  • Binding Sites, Antibody
  • CD4 Antigens / chemistry
  • CD4 Antigens / immunology
  • Epitopes / chemistry
  • Epitopes / immunology
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology
  • Molecular Docking Simulation*

Substances

  • Antibodies, Monoclonal
  • Antigen-Antibody Complex
  • CD4 Antigens
  • Epitopes
  • HIV Envelope Protein gp120
  • gp120 protein, Human immunodeficiency virus 1