Journal Article

Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

Lu, Jianming, Chen, Bing, Chen, Jia, Carfi, Andrea, Rits-Volloch, Sophia, Korber, Bette, Seaman, Michael S., Fredette, Nicholas, Linton, Christine E., Tian, Sai, Wagh, Kshitij, Harrison, Stephen C., Karaca-Griffin, Selen, Theiler, James, Cai, Yongfei

2017

Overview

The extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160)₃, cleaved to (gp120/gp41)₃] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length,membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160)₃, retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization by all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.

• Publisher: National Academy of Sciences,National Academy of Sciences, Washington, DC (United States)
• Subject: 60 APPLIED LIFE SCIENCES / Antibodies / Antibodies, Monoclonal / Antibodies, Neutralizing / Antigenic determinants / Antigenicity / Antigens / Antigens - chemistry / Antigens - metabolism / BASIC BIOLOGICAL SCIENCES / Biological Science / Biological Sciences / CD4 antigen / Clinical isolates / Conformation / Epitopes / Genetic diversity / Glycoprotein gp120 / Glycoprotein gp160 / Glycoprotein gp41 / HEK293 Cells / HIV / HIV Antibodies - immunology / HIV Envelope Protein gp120 - immunology / HIV Envelope Protein gp160 - immunology / HIV Envelope Protein gp160 - metabolism / HIV-1 - genetics / HIV-1 - metabolism / HIV-1 gp160 / Human immunodeficiency virus / Humans / Immunology and Inflammation / Medical treatment / Membranes / Neutralization / Neutralizing / neutralizing antibodies / Protein Conformation / Sensitivity / Trimers / vaccine design / Vaccine development / Vaccines / Virions / Viruses