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Human antibody response to Zika targets type-specific quaternary structure epitopes
Matthew H. Collins, … , Sean A. Diehl, Aravinda M. de Silva
Matthew H. Collins, … , Sean A. Diehl, Aravinda M. de Silva
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e124588. https://doi.org/10.1172/jci.insight.124588.
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Research Article Immunology Virology

Human antibody response to Zika targets type-specific quaternary structure epitopes

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Abstract

The recent Zika virus (ZIKV) epidemic in the Americas has revealed rare but serious manifestations of infection. ZIKV has emerged in regions endemic for dengue virus (DENV), a closely related mosquito-borne flavivirus. Cross-reactive antibodies confound studies of ZIKV epidemiology and pathogenesis. The immune responses to ZIKV may be different in people, depending on their DENV immune status. Here, we focus on the human B cell and antibody response to ZIKV as a primary flavivirus infection to define the properties of neutralizing and protective antibodies generated in the absence of preexisting immunity to DENV. The plasma antibody and memory B cell response is highly ZIKV type–specific, and ZIKV-neutralizing antibodies mainly target quaternary structure epitopes on the viral envelope. To map viral epitopes targeted by protective antibodies, we isolated 2 type-specific monoclonal antibodies (mAbs) from a ZIKV case. Both mAbs were strongly neutralizing in vitro and protective in vivo. The mAbs recognize distinct epitopes centered on domains I and II of the envelope protein. We also demonstrate that the epitopes of these mAbs define antigenic regions commonly targeted by plasma antibodies in individuals from endemic and nonendemic regions who have recovered from ZIKV infections.

Authors

Matthew H. Collins, Huy A. Tu, Ciara Gimblet-Ochieng, Guei-Jiun Alice Liou, Ramesh S. Jadi, Stefan W. Metz, Ashlie Thomas, Benjamin D. McElvany, Edgar Davidson, Benjamin J. Doranz, Yaoska Reyes, Natalie M. Bowman, Sylvia Becker-Dreps, Filemón Bucardo, Helen M. Lazear, Sean A. Diehl, Aravinda M. de Silva

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Figure 4

mAbs from primary ZIKV case exhibit potent ZIKV-specific neutralization and confer in vivo protection against lethal ZIKV challenge.

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mAbs from primary ZIKV case exhibit potent ZIKV-specific neutralization ...
(A) Antigen-capture ELISA for IgG binding was performed for 2 candidate ZIKV mAbs and 2 control mAbs (C10, ZIKV and DENV neutralizing; 2D22, DENV2 neutralizing) against DENV4 (left) and ZIKV (right). (B) Binding to ZIKV E monomers and EDI and EDIII was assessed for each mAb. (C) Competition assays (BOB) with a panel of mAbs with known binding specificities was performed to localize the epitopes of A9E and G9E. (D and E) FRNT assays against a panel of ZIKV strains and related flaviviruses were performed for A9E (D) and G9E (E). (F and G) Four- to 6-week-old Ifnar–/– mice were treated with 200 μg of indicated A9E, G9E, or polyclonal human IgG as a negative control on day –1 and challenged with 1,000 FFU of ZIKV (H/PF/2013). Weight loss (F) and mortality (G) were monitored for 14 days after infection. Results represent 6 to 7 mice per group combined from 2 independent experiments. Weights are shown as mean ± SEM and were censored upon the first death in the group. NA, not applicable.
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