Structural and molecular basis for Ebola virus neutralization by protective human antibodies

Misasi, John; Gilman, M.S.A.; Kanekiyo, Masaru; Gui, Miao; Cagigi, Alberto; Mulangu, Sabue; Corti, Davide; Ledgerwood, Julie E.; Lanzavecchia, Antonio; Cunningham, James M.; Muyembé-Tamfun, Jean Jacques; Baxa, Ulrich; Graham, Barney S.; Xiang, Ye; Sullivan, Nancy J.; McLellan, Jason S.

doi:10.1126/science.aad6117

Cited by 190 publications

(272 citation statements)

References 54 publications

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“…Strain-specific neutralization of G-specific antibodies correlates with epitope specificity. Antibody efficacy is determined by multiple variables, ranging from antibody and target glycosylation, binding on and off rate, the epitope, and the angle that the target is approached by the antibody (4,(22)(23)(24). Here, we hypothesized that for the G-specific antibodies, the neutralization potency may be determined by the binding site on the G protein.…”

Section: Resultsmentioning

confidence: 99%

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells

Cortjens

Yasuda

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) causes severe respiratory disease in young children. Antibodies specific for the RSV prefusion F protein have guided RSV vaccine research, and in human serum, these antibodies contribute to Ͼ90% of the neutralization response; however, detailed insight into the composition of the human B cell repertoire against RSV is still largely unknown. In order to study the B cell repertoire of three healthy donors for specificity against RSV, CD27 ϩ memory B cells were isolated and immortalized using BCL6 and Bcl-xL. Of the circulating memory B cells, 0.35% recognized RSV-A2-infected cells, of which 59% were IgAexpressing cells and 41% were IgG-expressing cells. When we generated monoclonal B cells selected for high binding to RSV-infected cells, 44.5% of IgGexpressing B cells and 56% of IgA-expressing B cells reacted to the F protein, while, unexpectedly, 41.5% of IgG-expressing B cells and 44% of IgA expressing B cells reacted to the G protein. Analysis of the G-specific antibodies revealed that 4 different domains on the G protein were recognized. These epitopes predicted cross-reactivity between RSV strain A (RSV-A) and RSV-B and matched the potency of antibodies to neutralize RSV in HEp-2 cells and in primary epithelial cell cultures. G-specific antibodies were also able to induce antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis of RSV-A2-infected cells. However, these processes did not seem to depend on a specific epitope. In conclusion, healthy adults harbor a diverse repertoire of RSV glycoprotein-specific antibodies with a broad range of effector functions that likely play an important role in antiviral immunity.IMPORTANCE Human RSV remains the most common cause of severe lower respiratory tract disease in premature babies, young infants, the elderly, and immunocompromised patients and plays an important role in asthma exacerbations. In developing countries, RSV lower respiratory tract disease has a high mortality. Without an effective vaccine, only passive immunization with palivizumab is approved for prophylactic treatment. However, highly potent RSV-specific monoclonal antibodies could potentially serve as a therapeutic treatment and contribute to disease control and mortality reduction. In addition, these antibodies could guide further vaccine development. In this study, we isolated and characterized several novel antibodies directed at the RSV G protein. This information can add to our understanding and treatment of RSV disease.

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Section: Resultsmentioning

confidence: 99%

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells

Cortjens

Yasuda

et al. 2017

J Virol

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“…Residue 544 lies at the base of an extended loop structure in GP2. Crystal structures of the EBOV Mayinga fusion loop in the prefusion state containing either threonine or isoleucine at position 544 are reported in the literature (18,19). We analyzed these structures and did not see a major structural difference between them, either globally or in the localized region of residue 544.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Mutation at Amino Acid 544 of the Ebola Virus Glycoprotein Potentiates Virus Entry and Selection in Tissue Culture

Ruedas

Ladner

Ettinger

et al. 2017

J Virol

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Ebolaviruses have a surface glycoprotein (GP 1,2 ) that is required for virus attachment and entry into cells. Mutations affecting GP 1,2 functions can alter virus growth properties. We generated a recombinant vesicular stomatitis virus encoding Ebola virus Makona variant GP 1,2 (rVSV-MAK-GP) and observed emergence of a T544I mutation in the Makona GP 1,2 gene during tissue culture passage in certain cell lines. The T544I mutation emerged within two passages when VSV-MAK-GP was grown on Vero E6, Vero, and BS-C-1 cells but not when it was passaged on Huh7 and HepG2 cells. The mutation led to a marked increase in virus growth kinetics and conferred a robust growth advantage over wild-type rVSV-MAK-GP on Vero E6 cells. Analysis of complete viral genomes collected from patients in western Africa indicated that this mutation was not found in Ebola virus clinical samples. However, we observed the emergence of T544I during serial passage of various Ebola Makona isolates on Vero E6 cells. Three independent isolates showed emergence of T544I from undetectable levels in nonpassaged virus or virus passaged once to frequencies of greater than 60% within a single passage, consistent with it being a tissue culture adaptation. Intriguingly, T544I is not found in any Sudan, Bundibugyo, or Tai Forest ebolavirus sequences. Furthermore, T544I did not emerge when we serially passaged recombinant VSV encoding GP 1,2 from these ebolaviruses. This report provides experimental evidence that the spontaneous mutation T544I is a tissue culture adaptation in certain cell lines and that it may be unique for the species Zaire ebolavirus. IMPORTANCE The Ebola virus (Zaire) species is the most lethal species of all ebolaviruses in terms of mortality rate and number of deaths. Understanding how the Ebola virus surface glycoprotein functions to facilitate entry in cells is an area of intense research. Recently, three groups independently identified a polymorphism in the Ebola glycoprotein (I544) that enhanced virus entry, but they did not agree in their conclusions regarding its impact on pathogenesis. Our findings here address the origins of this polymorphism and provide experimental evidence showing that it is the result of a spontaneous mutation (T544I) specific to tissue culture conditions, suggesting that it has no role in pathogenesis. We further show that this mutation may be unique to the species Zaire ebolavirus, as it does not occur in Sudan, Bundibugyo, and Tai Forest ebolaviruses. Understanding the mechanism behind this mutation can provide insight into functional differences that exist in culture conditions and among ebolavirus glycoproteins.

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“…One hypothesis that might be derived from these observations is that protective monotherapy may require both potent binding and complete complement-independent neutralization. In addition, mAb114's specific mechanism of neutralization [which targets an essential step in virus entry (20)] and observed in vitro ADCC activity may contribute to mAb114's ability to protect against lethal EVD in macaques.…”

Section: Research | Reportsmentioning

confidence: 99%

Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody

Corti

Misasi

Mulangu

et al. 2016

Science

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390

393

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Antibodies block Ebola virus entry The recent Ebola virus outbreak in West Africa illustrates the need for both an effective vaccine and therapies to treat infected individuals. Corti et al. isolated two monoclonal antibodies from a survivor of the 1995 Kikwit outbreak and demonstrated their therapeutic efficacy in Ebola virus–infected macaques. In fact, one antibody protected macaques when it was given up to 5 days after infection. Misasi et al. solved the crystal structures of fragments of the two antibodies bound to the Ebola virus glycoprotein (GP), which mediates viral cell entry. The two antibodies targeted different regions of GP, but in both cases blocked steps required for viral entry. Science , this issue pp. 1339 & 1343

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Structural and molecular basis for Ebola virus neutralization by protective human antibodies

Cited by 190 publications

References 54 publications

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells

Spontaneous Mutation at Amino Acid 544 of the Ebola Virus Glycoprotein Potentiates Virus Entry and Selection in Tissue Culture

Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody

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