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Structure. 2019 Jan 2;27(1):196-206.e6. doi: 10.1016/j.str.2018.10.007. Epub 2018 Nov 21.

Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition.

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gwo-yu.chuang@nih.gov.
2
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USA.
4
Department of Biochemistry and Molecular Biophysics & Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA.
5
National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USA.
6
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics & Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA.
7
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics & Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA. Electronic address: pdkwong@nih.gov.

Abstract

Over the past decade, structures have been determined for broadly neutralizing antibodies that recognize all major exposed surfaces of the prefusion-closed HIV-1-envelope (Env) trimer. To understand this recognition and its implications, we analyzed 206 antibody-HIV-1 Env structures from the Protein Data Bank with resolution suitable to define interaction chemistries and measured antibody neutralization on a 208-strain panel. Those with >25% breadth segregated into almost two dozen classes based on ontogeny and recognition and into six epitope categories based on recognized Env residues. For paratope, the number of protruding loops and level of somatic hypermutation were significantly higher for broad HIV-1 neutralizing antibodies than for a comparison set of non-HIV-1 antibodies (p < 0.0001). For epitope, the number of independent sequence segments was higher (p < 0.0001), as well as the glycan component surface area (p = 0.0005). The unusual characteristics of epitope and paratope delineated here are likely to reflect respectively virus-immune evasion and antibody-recognition solutions that allow effective neutralization of HIV-1.

KEYWORDS:

B cell ontogeny; X-ray crystallography; antibody recognition; broadly neutralizing antibody; cryo-electron microscopy; envelope glycoprotein trimer; glycan shielding; sequence variation; vaccine design

PMID:
30471922
DOI:
10.1016/j.str.2018.10.007

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