Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance
Justin R. Bailey, … , Steven K.H. Foung, Stuart C. Ray
Justin R. Bailey, … , Steven K.H. Foung, Stuart C. Ray
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):437-447. https://doi.org/10.1172/JCI78794.
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Research Article

Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance

Abstract

For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization panel expressing diverse, naturally occurring HCV envelopes (E1E2s) and used this panel to characterize neutralizing breadth and resistance mechanisms of 18 previously described broadly neutralizing anti-HCV human mAbs. The observed mAb resistance could not be attributed to polymorphisms in E1E2 at known mAb-binding residues. Additionally, hierarchical clustering analysis of neutralization resistance patterns revealed relationships between mAbs that were not predicted by prior epitope mapping, identifying 3 distinct neutralization clusters. Using this clustering analysis and envelope sequence data, we identified polymorphisms in E2 that confer resistance to multiple broadly neutralizing mAbs. These polymorphisms, which are not at mAb contact residues, also conferred resistance to neutralization by plasma from HCV-infected subjects. Together, our method of neutralization clustering with sequence analysis reveals that polymorphisms at noncontact residues may be a major immune evasion mechanism for HCV, facilitating viral persistence and presenting a challenge for HCV vaccine development.

Authors

Justin R. Bailey, Lisa N. Wasilewski, Anna E. Snider, Ramy El-Diwany, William O. Osburn, Zhenyong Keck, Steven K.H. Foung, Stuart C. Ray

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Figure 5

Polymorphisms between amino acids 526 and 569 (β-sheet) of resistant E1E2 clone 1a129 confer resistance to multiple broadly neutralizing mAbs.

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Polymorphisms between amino acids 526 and 569 (β-sheet) of resistant E1E...
(A) Crystal structure of H77 E2 core, published by Kong and colleagues (34), from the Protein Data Bank, accession 4MWF, with colors modified. E2 core front layer (amino acids 412–444) is cyan, β2-β5/partial CD81-binding loop (amino acids 445–525) is yellow, and partial CD81-binding loop/β6-β8 (amino acids 526–569) is red. Remaining structure is green. Residue 442 is marked in orange. (B) Neutralization by the indicated mAb of HCVpp with E1E2 chimeras between sensitive clone 1b09 and neutralization-resistant E1E2 clone 1a129. Chimeras with β6-β8 (1a129-β, amino acids 526–569) from resistant clone 1a129 are marked in red. Chimeras with the front layer, CD81-binding loop, and the central β-sheet (1a129-FCβ, amino acids 412–569) from resistant clone 1a129 are marked with cyan, yellow, and red. Dashed lines indicate 50% neutralization. Error bars indicate SD between duplicate wells.