Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis

Jing Jin, Nathan M. Liss, Dong Hua Chen, Maofu Liao, Julie M. Fox, Raeann M. Shimak, Rachel H. Fong, Daniel Chafets, Sonia Bakkour, Sheila Keating, Marina E. Fomin, Marcus O. Muench, Michael B. Sherman, Benjamin J. Doranz, Michael S. Diamond, Graham Simmons

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.

Original languageEnglish (US)
Pages (from-to)2553-2564
Number of pages12
JournalCell Reports
Volume13
Issue number11
DOIs
StatePublished - Dec 22 2015

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis'. Together they form a unique fingerprint.

Cite this