1. Paring down HIV-1 Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region
- Author
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Tolbert, William D., Gohain, Neelakshi, Veillette, Maxime, Chapleau, Jean-Philippe, Orlandi, Chiara, Visciano, Maria L., Ebadi, Maryam, DeVico, Anthony L., Fouts, Timothy R., Finzi, Andrés, Lewis, George K., and Pazgier, Marzena
- Subjects
Molecular Docking Simulation ,Epitopes ,CD4 Antigens ,Antibodies, Monoclonal ,Antigen-Antibody Complex ,Binding Sites, Antibody ,HIV Envelope Protein gp120 ,Article - 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.
- Published
- 2016