Structural basis of Chikungunya virus inhibition by monoclonal antibodies

Qun Fei Zhou, Julie M. Fox, James T. Earnest, Thiam Seng Ng, Arthur S. Kim, Guntur Fibriansah, Victor A. Kostyuchenko, Jian Shi, Bo Shu, Michael S. Diamond, Shee Mei Lok

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Chikungunya virus (CHIKV) is an emerging viral pathogen that causes both acute and chronic debilitating arthritis. Here, we describe the functional and structural basis as to how two anti-CHIKV monoclonal antibodies, CHK-124 and CHK-263, potently inhibit CHIKV infection in vitro and in vivo. Our in vitro studies show that CHK-124 and CHK-263 block CHIKV at multiple stages of viral infection. CHK-124 aggregates virus particles and blocks attachment. Also, due to antibody-induced virus aggregation, fusion with endosomes and egress are inhibited. CHK-263 neutralizes CHIKV infection mainly by blocking virus attachment and fusion. To determine the structural basis of neutralization, we generated cryogenic electron microscopy reconstructions of Fab:CHIKV complexes at 4- to 5-Å resolution. CHK-124 binds to the E2 domain B and overlaps with the Mxra8 receptor-binding site. CHK-263 blocks fusion by binding an epitope that spans across E1 and E2 and locks the heterodimer together, likely preventing structural rearrangements required for fusion. These results provide structural insight as to how neutralizing antibody engagement of CHIKV inhibits different stages of the viral life cycle, which could inform vaccine and therapeutic design.

Original languageEnglish
Pages (from-to)27637-27645
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number44
DOIs
StatePublished - Nov 3 2020

Keywords

  • Antibody
  • Chikungunya virus
  • Cryo-EM
  • Epitope

Fingerprint

Dive into the research topics of 'Structural basis of Chikungunya virus inhibition by monoclonal antibodies'. Together they form a unique fingerprint.

Cite this