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Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site
Hao D. Cheng, … , Chris Bailey-Kellogg, Margaret E. Ackerman
Hao D. Cheng, … , Chris Bailey-Kellogg, Margaret E. Ackerman
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e97018. https://doi.org/10.1172/jci.insight.97018.
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Resource and Technical Advance AIDS/HIV Vaccines

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

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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.

Authors

Hao D. Cheng, Sebastian K. Grimm, Morgan S.A. Gilman, Luc Christian Gwom, Devin Sok, Christopher Sundling, Gina Donofrio, Gunilla B. Karlsson Hedestam, Mattia Bonsignori, Barton F. Haynes, Timothy P. Lahey, Isaac Maro, C. Fordham von Reyn, Miroslaw K. Gorny, Susan Zolla-Pazner, Bruce D. Walker, Galit Alter, Dennis R. Burton, Merlin L. Robb, Shelly J. Krebs, Michael S. Seaman, Chris Bailey-Kellogg, Margaret E. Ackerman

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Figure 1

Epitope mapping of CD4bs antibodies.

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Epitope mapping of CD4bs antibodies.
A panel of gp120 core point mutants...
A panel of gp120 core point mutants was used to epitope map CD4bs antibodies (n = 25). Representative mAbs from 4 groups, including weakly neutralizing (wnAbs), vaccine-induced, and broadly neutralizing (bnAb) antibodies were evaluated. (A) The sensitivity of various mAbs to mutation of core residues is plotted on a structural representation. The CD4bs is colored green, and tolerated point mutations are colored black, while substitutions driving reduced (<80%; light blue to red) or strongly enhanced (>160%; blue) binding to the core relative to WT are indicated. (B) Heatmap representation of the epitope-mapping results observed for the set of CD4bs mAbs. Hierarchical clustering identifies major subgroups of CD4bs mAbs that are associated with neutralization breadth and potency. The color bar at top indicates the class of core: core variants with substitutions made in CD4bs residues are indicated in green, core variants with substitutions made in other sites on the core indicated are indicated in black, and the unmutated WT core are indicated in gray. The color bar at the left indicates the mAb class, with bnAbs indicated in black and non-bnAbs indicated in shades of gray (vaccine-induced antibodies in light gray, infection-induced antibodies in dark gray).

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