The Fc region of an antibody impacts the neutralization of West Nile viruses in different maturation states

Phong D. Lee, Swati Mukherjee, Melissa A. Edeling, Kimberly A. Dowd, S. K. Austin S. Kyle, Carolyn J. Manhart, Michael S. Diamond, Daved H. Fremont, Theodore C. Pierson

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Flavivirus-infected cells secrete a structurally heterogeneous population of viruses because of an inefficient virion maturation process. Flaviviruses assemble as noninfectious, immature virions composed of trimers of envelope (E) and precursor membrane (prM) protein heterodimers. Cleavage of prM is a required process during virion maturation, although this often remains incomplete for infectious virus particles. Previous work demonstrated that the efficiency of virion maturation could impact antibody neutralization through changes in the accessibility of otherwise cryptic epitopes on the virion. In this study, we show that the neutralization potency of monoclonal antibody (MAb) E33 is sensitive to the maturation state of West Nile virus (WNV), despite its recognition of an accessible epitope, the domain III lateral ridge (DIII-LR). Comprehensive epitope mapping studies with 166 E protein DIII-LR variants revealed that the functional footprint of MAb E33 on the E protein differs subtly from that of the well-characterized DIII-LR MAb E16. Remarkably, aromatic substitutions at E protein residue 306 ablated the maturation state sensitivity of E33 IgG, and the neutralization efficacy of E33 Fab fragments was not affected by changes in the virion maturation state. We propose that E33 IgG binding on mature virions orients the Fc region in a manner that impacts subsequent antibody binding to nearby sites. This Fc-mediated steric constraint is a novel mechanism by which the maturation state of a virion modulates the efficacy of the humoral immune response to flavivirus infection.

Original languageEnglish
Pages (from-to)13729-13740
Number of pages12
JournalJournal of virology
Volume87
Issue number24
DOIs
StatePublished - Dec 2013

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