Journal Article

Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site

Gristick, Harry B, von Boehmer, Lotta, Schamber, Michael, Bjorkman, Pamela J, West Jr, Anthony P, Nussenzweig, Michel C, Gazumyan, Anna, Fätkenheuer, Gerd, Seaman, Michael S, Golijanin, Jovana, Klein, Florian

2016

Overview

Crystal structures of HIV Env trimer with native glycosylation in complex with neutralizing antibodies reveal a glycan shield of high-mannose and complex-type N-glycan and indicate a path for germline-targeting vaccine design. HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-Å- and 3.9-Å-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs. Env trimer was complexed with 10-1074 (against the V3-loop) and IOMA, a new CD4-binding site (CD4bs) antibody. Although IOMA derives from VH1-2*02, the germline gene of CD4bs-targeting VRC01-class bNAbs, its light chain lacks the short CDRL3 that defines VRC01-class bNAbs. Thus IOMA resembles 8ANC131-class/VH1-46–derived CD4bs bNAbs, which have normal-length CDRL3s. The existence of bNAbs that combine features of VRC01-class and 8ANC131-class antibodies has implications for immunization strategies targeting VRC01-like bNAbs.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250 / 631/45/612/1231 / 631/535/1266 / Analysis / Antibodies / Antibodies, Neutralizing - chemistry / Antibodies, Neutralizing - immunology / Binding sites / Biochemistry / Biological Microscopy / CD4 Antigens - chemistry / CD4 Antigens - immunology / CD4 lymphocytes / Chemical properties / Crystal structure / Crystallography, X-Ray / Epitopes - analysis / Epitopes - immunology / Glycosylation / Heterogeneity / HIV / HIV (Viruses) / HIV Antibodies - chemistry / HIV Antibodies - immunology / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - immunology / HIV Infections - immunology / HIV Infections - virology / HIV-1 - chemistry / HIV-1 - immunology / Human immunodeficiency virus / Humans / Immunization / Immunoglobulins / Lentivirus / Life Sciences / Mannose - analysis / Mannose - immunology / Membrane Biology / Models, Molecular / Polysaccharides - analysis / Polysaccharides - immunology / Protein Conformation / Protein Multimerization / Protein Structure / Vaccines / Viral antibodies