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JCI Insight. 2018 Mar 8;3(5). pii: 97018. doi: 10.1172/jci.insight.97018.

Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site.

Author information

1
Thayer School of Engineering and.
2
Molecular and Cellular Biology Program, Dartmouth College, Hanover, New Hampshire, USA.
3
Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon.
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.
5
Unit of Infectious Diseases, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden.
6
US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
7
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
8
Duke Human Vaccine Institute, Durham, North Carolina, USA.
9
Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
10
DarDar Health Programs, Dar es salaam, Tanzania.
11
Tokyo Medical and Dental University, Tokyo, Japan.
12
Department of Pathology, NYU School of Medicine, New York, New York, USA.
13
Departments of Medicine and Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
14
Ragon Institute of MGH, MIT, and Harvard University, Cambridge, Massachusetts, USA.
15
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
16
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
17
Department of Computer Science, Dartmouth College, Hanover, New Hampshire, USA.

Abstract

Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs-specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades.

KEYWORDS:

AIDS vaccine; AIDS/HIV; Adaptive immunity; Immunoglobulins; Vaccines

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