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TitleStructural basis of Chikungunya virus inhibition by monoclonal antibodies.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 117, Issue 44, Page 27637-27645, Year 2020
Publish dateNov 3, 2020
AuthorsQun 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 /
PubMed AbstractChikungunya 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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:33087569 / PubMed Central
MethodsEM (single particle)
Resolution4.5 - 9.4 Å
Structure data

30476

7cvy

EMDB-30476, PDB-7cvy:
Cryo-EM structure of Chikungunya virus in complex with Fab fragments of mAb CHK-124
Method: EM (single particle) / Resolution: 5.2 Å

30477

7cvz

EMDB-30477, PDB-7cvz:
Cryo-EM structure of Chikungunya virus in complex with Fab fragments of mAb CHK-263
Method: EM (single particle) / Resolution: 4.7 Å

30478

7cw0

EMDB-30478, PDB-7cw0:
Cryo-EM structure of Chikungunya virus in complex with mAb CHK-263 IgG
Method: EM (single particle) / Resolution: 5.9 Å

30479

7cw2

EMDB-30479, PDB-7cw2:
Cryo-EM structure of Chikungunya virus in complex with Fab fragments of mAb CHK-263 (subregion around icosahedral 5-fold vertex)
Method: EM (single particle) / Resolution: 4.5 Å

30480

7cw3

EMDB-30480, PDB-7cw3:
Cryo-EM structure of Chikungunya virus in complex with mAb CHK-263 IgG (subregion around icosahedral 2-fold vertex)
Method: EM (single particle) / Resolution: 9.4 Å

Source
  • chikungunya virus
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM/VIRUS / CHIKV / Fab / complex / VIRUS / IMMUNE SYSTEM-VIRUS complex / VIRUS/IMMUNE SYSTEM / VIRUS-IMMUNE SYSTEM complex / IgG / localized reconstruction

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