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2015 ; 112
(45
): 13898-903
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Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human
monoclonal antibodies with therapeutic activity
#MMPMID26504196
Long F
; Fong RH
; Austin SK
; Chen Z
; Klose T
; Fokine A
; Liu Y
; Porta J
; Sapparapu G
; Akahata W
; Doranz BJ
; Crowe JE Jr
; Diamond MS
; Rossmann MG
Proc Natl Acad Sci U S A
2015[Nov]; 112
(45
): 13898-903
PMID26504196
show ga
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe
acute and chronic disease in humans. Although highly inhibitory murine and human
monoclonal antibodies (mAbs) have been generated, the structural basis of their
neutralizing activity remains poorly characterized. Here, we determined the
cryo-EM structures of chikungunya virus-like particles complexed with antibody
fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block
virus fusion with host membranes. Both mAbs bind primarily to sites within the A
and B domains, as well as to the B domain's ?-ribbon connector of the viral
glycoprotein E2. The footprints of these antibodies on the viral surface were
consistent with results from loss-of-binding studies using an alanine scanning
mutagenesis-based epitope mapping approach. The Fab fragments stabilized the
position of the B domain relative to the virus, particularly for the complex with
5M16. This finding is consistent with a mechanism of neutralization in which
anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain
away from the underlying fusion loop on the E1 glycoprotein and therefore block
the requisite pH-dependent fusion of viral and host membranes.
|Antibodies, Monoclonal/chemistry/*immunology/therapeutic use
[MESH]
|Antibodies, Neutralizing/chemistry/*immunology/therapeutic use
[MESH]