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Nat Struct Mol Biol. 2016 Oct;23(10):906-915. doi: 10.1038/nsmb.3291. Epub 2016 Sep 12.

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

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
2
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.
3
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
4
Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany.
5
German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
6
Laboratory of Experimental Immunology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
7
Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany.
8
Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.

Abstract

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.

PMID:
27617431
PMCID:
PMC5127623
[Available on 2017-04-01]
DOI:
10.1038/nsmb.3291
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