PMID- 30206174
OWN - NLM
STAT- MEDLINE
DCOM- 20190304
LR  - 20230928
IS  - 2150-7511 (Electronic)
VI  - 9
IP  - 5
DP  - 2018 Sep 11
TI  - Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a 
      Conserved, yet Cryptic Epitope.
LID - 10.1128/mBio.01674-18 [doi]
LID - e01674-18
AB  - Only one naturally occurring human antibody has been described thus far that is 
      capable of potently neutralizing all five ebolaviruses. Here we present two 
      crystal structures of this rare, pan-ebolavirus neutralizing human antibody in 
      complex with Ebola virus and Bundibugyo virus glycoproteins (GPs), respectively. 
      The structures delineate the key protein and glycan contacts for binding that are 
      conserved across the ebolaviruses, explain the antibody's unique broad 
      specificity and neutralization activity, and reveal the likely mechanism behind a 
      known escape mutation in the fusion loop region of GP2. We found that the epitope 
      of this antibody, ADI-15878, extends along the hydrophobic paddle of the fusion 
      loop and then dips down into a highly conserved pocket beneath the N-terminal 
      tail of GP2, a mode of recognition unlike any other antibody elicited against 
      Ebola virus, and likely critical for its broad activity. The fold of Bundibugyo 
      virus glycoprotein, not previously visualized, is similar to the fold of Ebola 
      virus GP, and ADI-15878 binds to each virus's GP with a similar strategy and 
      angle of attack. These findings will be useful in deployment of this antibody as 
      a broad-spectrum therapeutic and in the design of immunogens that elicit the 
      desired broadly neutralizing immune response against all members of the 
      ebolavirus genus and filovirus family.IMPORTANCE There are five different members 
      of the Ebolavirus genus. Provision of vaccines and treatments able to protect 
      against any of the five ebolaviruses is an important goal of public health. 
      Antibodies are a desired result of vaccines and can be delivered directly as 
      therapeutics. Most antibodies, however, are effective against only one or two, 
      not all, of these pathogens. Only one human antibody has been thus far described 
      to neutralize all five ebolaviruses, antibody ADI-15878. Here we describe the 
      molecular structure of ADI-15878 bound to the relevant target proteins of Ebola 
      virus and Bundibugyo virus. We explain how it achieves its rare breadth of 
      activity and propose strategies to design improved vaccines capable of eliciting 
      more antibodies like ADI-15878.
CI  - Copyright (c) 2018 West et al.
FAU - West, Brandyn R
AU  - West BR
AUID- ORCID: 0000-0002-1399-0117
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA.
FAU - Moyer, Crystal L
AU  - Moyer CL
AUID- ORCID: 0000-0002-0398-6392
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA.
FAU - King, Liam B
AU  - King LB
AUID- ORCID: 0000-0002-6816-3784
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA.
FAU - Fusco, Marnie L
AU  - Fusco ML
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA.
FAU - Milligan, Jacob C
AU  - Milligan JC
AUID- ORCID: 0000-0002-9369-0025
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA.
FAU - Hui, Sean
AU  - Hui S
AUID- ORCID: 0000-0002-9870-6823
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA.
FAU - Saphire, Erica Ollmann
AU  - Saphire EO
AUID- ORCID: 0000-0002-1206-7451
AD  - Department of Immunology and Microbiology, Scripps Research, La Jolla, 
      California, USA erica@scripps.edu.
AD  - Skaggs Institute for Chemical Biology, Scripps Research, La Jolla, California, 
      USA.
LA  - eng
GR  - T32 AI007354/AI/NIAID NIH HHS/United States
GR  - U19 AI109762/AI/NIAID NIH HHS/United States
GR  - R01 AI132204/AI/NIAID NIH HHS/United States
GR  - P41 GM103393/GM/NIGMS NIH HHS/United States
GR  - T32 GM007198/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180911
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antibodies, Viral)
RN  - 0 (Epitopes)
RN  - 0 (Glycoproteins)
RN  - 0 (Viral Envelope Proteins)
SB  - IM
CIN - mBio. 2018 Nov 20;9(6):. PMID: 30459187
MH  - Antibodies, Neutralizing/*immunology
MH  - Antibodies, Viral/*immunology
MH  - Ebolavirus/*immunology
MH  - Epitopes/immunology
MH  - Glycoproteins/*immunology
MH  - Humans
MH  - Protein Conformation
MH  - Viral Envelope Proteins/immunology
PMC - PMC6134094
OTO - NOTNLM
OT  - Bundibugyo virus
OT  - Ebola virus
OT  - antibody
OT  - broadly neutralizing
OT  - glycoprotein
OT  - pan-ebolavirus
OT  - structure
EDAT- 2018/09/13 06:00
MHDA- 2019/03/05 06:00
PMCR- 2018/09/11
CRDT- 2018/09/13 06:00
PHST- 2018/09/13 06:00 [entrez]
PHST- 2018/09/13 06:00 [pubmed]
PHST- 2019/03/05 06:00 [medline]
PHST- 2018/09/11 00:00 [pmc-release]
AID - mBio.01674-18 [pii]
AID - mBio01674-18 [pii]
AID - 10.1128/mBio.01674-18 [doi]
PST - epublish
SO  - mBio. 2018 Sep 11;9(5):e01674-18. doi: 10.1128/mBio.01674-18.