Structural basis for differential neutralization of ebolaviruses.

Abstract

There are five antigenically distinct ebolaviruses that cause hemorrhagic fever in humans or non-human primates (Ebola virus, Sudan virus, Reston virus, Taï Forest virus, and Bundibugyo virus). The small handful of antibodies known to neutralize the ebolaviruses bind to the surface glycoprotein termed GP₁,₂. Curiously, some antibodies against them are known to neutralize in vitro but not protect in vivo, whereas other antibodies are known to protect animal models in vivo, but not neutralize in vitro. A detailed understanding of what constitutes a neutralizing and/or protective antibody response is critical for development of novel therapeutic strategies. Here, we show that paradoxically, a lower affinity antibody with restricted access to its epitope confers better neutralization than a higher affinity antibody against a similar epitope, suggesting that either subtle differences in epitope, or different characteristics of the GP₁,₂ molecules themselves, confer differential neutralization susceptibility. Here, we also report the crystal structure of trimeric, prefusion GP₁,₂ from the original 1976 Boniface variant of Sudan virus complexed with 16F6, the first antibody known to neutralize Sudan virus, and compare the structure to that of Sudan virus, variant Gulu. We discuss new structural details of the GP₁-GP₂ clamp, thermal motion of various regions in GP₁,₂ across the two viruses visualized, details of differential interaction of the crystallized neutralizing antibodies, and their relevance for virus neutralization.

• Authors: Shridhar Bale, Joao M Dias, Marnie L Fusco, Takao Hashiguchi, Anthony C Wong, Tong Liu, Ana I Keuhne, Sheng Li, Virgil L Woods Jr, Kartik Chandran, John M Dye, Erica Ollmann Saphire
• Journal: Viruses (Viruses) Vol. 4 Issue 4 Pg. 447-70 (04 2012) ISSN: 1999-4915 [Electronic] Switzerland
• PMID: 22590681 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Epitopes
• Viral Envelope Proteins
• envelope glycoprotein, Ebola virus

Topics

• Antibodies, Neutralizing (chemistry, immunology)
• Antibodies, Viral (chemistry, immunology)
• Antibody Affinity
• Crystallography, X-Ray
• Ebolavirus (immunology)
• Epitopes
• Models, Molecular
• Neutralization Tests
• Protein Binding
• Protein Structure, Quaternary
• Viral Envelope Proteins (chemistry, immunology)