Abstract
The Zika virus (ZIKV), a flavivirus transmitted by Aedes mosquitoes, has emerged as a global public health concern. Pre-existing cross-reactive antibodies against other flaviviruses could modulate immune responses to ZIKV infection by antibody-dependent enhancement, highlighting the importance of understanding the immunogenicity of the ZIKV envelope protein. In this study, we identified a panel of human monoclonal antibodies (mAbs) that target domain III (DIII) of the ZIKV envelope protein from a very large phage-display naive antibody library. These germline-like antibodies, sharing 98%–100% hoLogy with their corresponding germline IGHV genes, bound ZIKV DIII specifically with high affinities. One mAb, m301, broadly neutralized the currently circulating ZIKV strains and showed a synergistic effect with another mAb, m302, in neutralizing ZIKV in vitro and in a mouse model of ZIKV infection. Interestingly, epitope mapping and competitive binding studies suggest that m301 and m302 bind adjacent regions of the DIII C–C′ loop, which represents a recently identified cryptic epitope that is intermittently exposed in an uncharacterized virus conformation. This study extended our understanding of antigenic epitopes of ZIKV antibodies and has direct implications for the design of ZIKV vaccines.Emerging Microbes & Infections (2017) 6, e89; doi:10.1038/emi.2017.79; published online 11 October 2017
Highlights
The Zika virus (ZIKV) is a re-emerging mosquito-borne enveloped virus belonging to the genus Flavivirus, a genus that has recently received considerable attention owing to the rapidly increasing incidence of dengue (DENV), yellow fever, West Nile, and tickborne encephalitis virus infections.[1]
We identified a panel of human monoclonal antibodies that target domain III (DIII) of the ZIKV envelope protein from a very large phage-display naive antibody library
All antibodies were reactive to recombinant DIII or E glycoprotein in Western blot analyses, suggesting that m301–m304 monoclonal antibodies (mAbs) might recognize linear epitopes on ZIKV DIII (Figure 1D)
Summary
The Zika virus (ZIKV) is a re-emerging mosquito-borne enveloped virus belonging to the genus Flavivirus, a genus that has recently received considerable attention owing to the rapidly increasing incidence of dengue (DENV), yellow fever, West Nile, and tickborne encephalitis virus infections.[1]. Understanding the human antibody response to ZIKV is central to the development of effective vaccines and serodiagnostics.[9,10,11,12] Threedimensional cryo-electron microscopy structures of ZIKV reveal that it shares a high structural similarity to other flaviviruses with known structures.[13,14] The ZIKV envelope (E) glycoprotein, which was found to be a dimer on the surface of a mature virion, mediates viral entry, membrane fusion, and serves as the major target for neutralizing antibodies.[15] Recent studies have revealed that critical targets of neutralizing antibody responses to flaviviruses are conformational or quaternary epitopes that require higher-order structures not presented on E monomers.[16,17,18] Similar to other flaviviruses, the E protein of ZIKV comprises three domains: a central β-barrel domain (domain I, DI), an extended dimerization domain (domain II, DII), and an immunoglobulin-like domain (domain III, DIII). Previous studies on DENV-challenged mice showed that DIII-specific antibodies form a significant fraction of neutralizing antibodies and possess highly neutralizing activity.[19,20] Intriguingly, it was found that the neutralizing human antibodies mainly recognize quaternary structuredependent epitopes presented on the intact virion in human immune sera;[21] the majority of antibodies produced during a primary
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