Asymmetric antiviral effects of ebolavirus antibodies targeting glycoprotein stem and glycan cap.
Asymmetric antiviral effects of ebolavirus antibodies targeting glycoprotein stem and glycan cap.
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DOI：
10.1371/journal.ppat.1007204
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发表时间：
2018-08
期刊：
影响因子：
6.7
通讯作者：
Bukreyev A
中科院分区：
文献类型：
--
作者：
Ilinykh PA;Santos RI;Gunn BM;Kuzmina NA;Shen X;Huang K;Gilchuk P;Flyak AI;Younan P;Alter G;Crowe JE Jr;Bukreyev A
Recent studies suggest that some monoclonal antibodies (mAbs) specific for ebolavirus glycoprotein (GP) can protect experimental animals against infections. Most mAbs isolated from ebolavirus survivors appeared to target the glycan cap or the stalk region of the viral GP, which is the envelope protein and the only antigen inducing virus-neutralizing antibody response. Some of the mAbs were demonstrated to be protective in vivo. Here, a panel of mAbs from four individual survivors of ebolavirus infection that target the glycan cap or stem region were selected for investigation of the mechanisms of their antiviral effect. Comparative characterization of the inhibiting effects on multiple steps of viral replication was performed, including attachment, post-attachment, entry, binding at low pH, post-cleavage neutralization of virions, viral trafficking to endosomes, cell-to-cell transmission, viral egress, and inhibition when added early at various time points post-infection. In addition, Fc-domain related properties were characterized, including activation and degranulation of NK cells, antibody-dependent cellular phagocytosis and glycan content. The two groups of mAbs (glycan cap versus stem) demonstrated very different profiles of activities suggesting usage of mAbs with different epitope specificity could coordinate inhibition of multiple steps of filovirus infection through Fab- and Fc-mediated mechanisms, and provide a reliable therapeutic approach. Recent progress in isolation of mAbs from survivors of filovirus infections suggests that the human adaptive immune system is capable of producing strong antibody responses. However, the effects of mAbs with different epitope specificity on individual steps of filovirus infection are still unclear. We evaluated a panel of mAbs obtained from survivors of natural filovirus infections, specific for the glycan cap or stem region of GP, for their effects on the attachment of viral particles to the cell surface, intracellular traffic of viral particles, proteolytic processing of GP, its interaction with the NPC1 receptor, cell-to-cell virus transmission, virus egress from infected cells, activation of natural killer cells and antibody-dependent cellular phagocytosis through Fc-mediated mechanisms. We found that antiviral activity of glycan cap-specific antibodies results from inhibition of attachment, cell-to-cell transmission and inhibition of virion budding. In contrast, the antiviral mechanisms of stem-specific antibodies were found to be inhibition of virus release from endosomal network to the cytoplasm, and also activation of natural killer cells and phagocytosis mediated by monocytes and neutrophils. The data provide new insight into the development of immune protective mechanisms during natural human infection, and have important implications for the treatment of filovirus infections by passively-transferred antibodies and vaccine design.
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影响因子：
64.5
作者：
Flyak AI;Shen X;Murin CD;Turner HL;David JA;Fusco ML;Lampley R;Kose N;Ilinykh PA;Kuzmina N;Branchizio A;King H;Brown L;Bryan C;Davidson E;Doranz BJ;Slaughter JC;Sapparapu G;Klages C;Ksiazek TG;Saphire EO;Ward AB;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
DOI：
10.1056/nejmoa1604330
发表时间：
2016-10-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
PREVAIL II Writing Group;Multi-National PREVAIL II Study Team;Davey RT Jr;Dodd L;Proschan MA;Neaton J;Neuhaus Nordwall J;Koopmeiners JS;Beigel J;Tierney J;Lane HC;Fauci AS;Massaquoi MBF;Sahr F;Malvy D
通讯作者：
Malvy D
影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
DOI：
10.1126/science.aaa8651
发表时间：
2015-07-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fibriansah G;Ibarra KD;Ng TS;Smith SA;Tan JL;Lim XN;Ooi JS;Kostyuchenko VA;Wang J;de Silva AM;Harris E;Crowe JE Jr;Lok SM
通讯作者：
Lok SM
DOI：
10.1073/pnas.1609316113
发表时间：
2016-10-18
影响因子：
11.1
作者：
He, Wenqian;Tan, Gene S.;Miller, Matthew S.
通讯作者：
Miller, Matthew S.