Journal article
Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance
The Journal of clinical investigation, Vol.125(1), pp.437-447
01/01/2015
DOI: 10.1172/JCI78794
PMCID: PMC4382262
PMID: 25500884
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.
Details
- Title: Subtitle
- Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance
- Creators
- Justin R. Bailey - Johns Hopkins UniversityLisa N. Wasilewski - Johns Hopkins UniversityAnna E. Snider - Johns Hopkins UniversityRamy El-Diwany - Johns Hopkins UniversityWilliam O. Osburn - Johns Hopkins UniversityZhenyong Keck - Stanford UniversitySteven K. H. Foung - Stanford UniversityStuart C. Ray - Johns Hopkins University
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(1), pp.437-447
- DOI
- 10.1172/JCI78794
- PMID
- 25500884
- PMCID
- PMC4382262
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 11
- Grant note
- T32GM007309 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 1K08 AI102761; U19 AI088791; R37 DA013806 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1P30AI094189 / Johns Hopkins University Center for AIDS Research R37DA013806 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission P30AI094189 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Surgery
- Record Identifier
- 9984966856602771
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