Journal Article

Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer

Acharya, Priyamvada, Kwong, Peter D, Zhang, Peng, Dolan, Michael A, Kwon, Alice, Lusso, Paolo, Guzzo, Christina, Liu, Qingbo, Gururani, Deepali, Chuang, Gwo-Yu, Bylund, Tatsiana, Zhou, Tongqing, Potter, Clinton S, Lu, Jacky, Carragher, Bridget, Miao, Huiyi, Wigge, Christoph, Druz, Aliaksandr, Rice, William J

2017

Overview

Cryo-EM analyses of the initial contact of the HIV-1 Env trimer with the CD4 receptor reveal that CD4 interacts with two gp120 protomers; these quaternary contacts are important for viral infectivity. Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1–Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurred after the mutation of CD4 residues that interact with CD4-BS2. Our results document the critical role of quaternary interactions in the initial HIV-Env-receptor contact, with implications for treatment and vaccine design.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/28 / 13 / 13/1 / 13/109 / 13/31 / 13/44 / 631/326/596 / 631/535/1258/1259 / 692/699 / 82 / 82/103 / 82/80 / 82/83 / Amino Acid Sequence / Antibodies / Antibodies, Neutralizing - chemistry / Antibodies, Neutralizing - metabolism / Binding Sites / Biochemistry / Biological Microscopy / CD4 antigen / CD4 Antigens - chemistry / CD4 Antigens - metabolism / CD4 Antigens - ultrastructure / CD4 lymphocytes / Coalescence / Cryoelectron Microscopy / Electron microscopy / Genetic aspects / Glycoprotein gp120 / Glycoproteins / Health aspects / HEK293 Cells / HIV / HIV Antibodies - chemistry / HIV Antibodies - metabolism / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - metabolism / HIV Envelope Protein gp120 - ultrastructure / HIV Infections - metabolism / HIV-1 - metabolism / Human immunodeficiency virus / Humans / Infectious diseases / Infectivity / Kinetics / Life Sciences / Membrane Biology / Microscopy / Mutagenesis / Promoters (Genetics) / Properties / Protein Binding / Protein Multimerization / Protein Stability / Protein Structure / Protein Structure, Quaternary / Receptors / Surface Plasmon Resonance / Trimers / Vaccines