National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
U54 AI 057157
米国
引用
ジャーナル: PLoS Pathog / 年: 2021 タイトル: Antibody affinity versus dengue morphology influences neutralization. 著者: Guntur Fibriansah / Elisa X Y Lim / Jan K Marzinek / Thiam-Seng Ng / Joanne L Tan / Roland G Huber / Xin-Ni Lim / Valerie S Y Chew / Victor A Kostyuchenko / Jian Shi / Ganesh S Anand / Peter ...著者: Guntur Fibriansah / Elisa X Y Lim / Jan K Marzinek / Thiam-Seng Ng / Joanne L Tan / Roland G Huber / Xin-Ni Lim / Valerie S Y Chew / Victor A Kostyuchenko / Jian Shi / Ganesh S Anand / Peter J Bond / James E Crowe / Shee-Mei Lok / 要旨: Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the ...Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the neutralizing properties of a serotype cross-reactive human monoclonal antibody (HMAb) 1C19 for strains with differing morphologies within the DENV1 and DENV2 serotypes. We mapped the 1C19 epitope to E protein domain II by hydrogen deuterium exchange mass spectrometry, cryoEM and molecular dynamics simulations, revealing that this epitope is likely partially hidden on the virus surface. We showed the antibody has high affinity for binding to recombinant DENV1 E proteins compared to those of DENV2, consistent with its strong neutralizing activities for all DENV1 strains tested regardless of their morphologies. This finding suggests that the antibody could out-compete E-to-E interaction for binding to its epitope. In contrast, for DENV2, HMAb 1C19 can only neutralize when the epitope becomes exposed on the bumpy-surfaced particle. Although HMAb 1C19 is not a suitable therapeutic candidate, this study with HMAb 1C19 shows the importance of choosing a high-affinity antibody that could neutralize diverse dengue virus morphologies for therapeutic purposes.
A: envelope protein B: envelope protein C: envelope protein H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
A: envelope protein B: envelope protein C: envelope protein H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
A: envelope protein B: envelope protein C: envelope protein H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
x 5
icosahedral pentamer
932 kDa, 25 ポリマー
分子量 (理論値)
分子数
合計 (水以外)
932,425
25
ポリマ-
932,425
25
非ポリマー
0
0
水
0
タイプ
名称
対称操作
数
identity operation
1_555
x,y,z
1
point symmetry operation
4
4
A: envelope protein B: envelope protein C: envelope protein H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
pH: 8 詳細: NTE buffer (12 mM Tris-HCl pH 8.0, 120 mM NaCl and 1 mM EDTA)
試料
包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: The purified virus was incubated with Fab 1C19 at 37 deg C for 30 min with a molar ratio of one Fab for every E-protein and followed by incubation at 4 deg C for 2 h.