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

TitleFine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site.
Publication TypeJournal Article
Year of Publication2018
AuthorsCheng HD, Grimm SK, Gilman MSa, Gwom LChristian, Sok D, Sundling C, Donofrio G, Karlsson Hedestam GB, Bonsignori M, Haynes BF, Lahey TP, Maro I, C von Reyn F, Gorny MK, Zolla-Pazner S, Walker BD, Alter G, Burton DR, Robb ML, Krebs SJ, Seaman MS, Bailey-Kellogg C, Ackerman ME
JournalJCI Insight
Volume3
Issue5
Date Published03/08/2018
ISSN2379-3708
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.

DOI10.1172/jci.insight.97018
Alternate JournalJCI Insight
PubMed ID29515029
PubMed Central IDPMC5922287
Grant ListUM1 AI100645 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
R01 AI102691 / AI / NIAID NIH HHS / United States
P01 AI120756 / AI / NIAID NIH HHS / United States
D43 TW009573 / TW / FIC NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
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