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.
Keywords: Filovirus; Ebola; ebolavirus; Sudan virus; neutralization: glycoprotein; antibodies; structure
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Bale, S.; Dias, J.M.; Fusco, M.L.; Hashiguchi, T.; Wong, A.C.; Liu, T.; Keuhne, A.I.; Li, S.; Woods, V.L., Jr.; Chandran, K.; Dye, J.M.; Saphire, E.O. Structural Basis for Differential Neutralization of Ebolaviruses. Viruses 2012, 4, 447-470.
Bale S, Dias JM, Fusco ML, Hashiguchi T, Wong AC, Liu T, Keuhne AI, Li S, Woods VL, Jr, Chandran K, Dye JM, Saphire EO. Structural Basis for Differential Neutralization of Ebolaviruses. Viruses. 2012; 4(4):447-470.
Bale, Shridhar; Dias, Joao M.; Fusco, Marnie L.; Hashiguchi, Takao; Wong, Anthony C.; Liu, Tong; Keuhne, Ana I.; Li, Sheng; Woods, Virgil L., Jr.; Chandran, Kartik; Dye, John M.; Saphire, Erica Ollmann. 2012. "Structural Basis for Differential Neutralization of Ebolaviruses." Viruses 4, no. 4: 447-470.