Structural basis of potent Zika–dengue virus antibody cross-neutralization

Abstract

Zika virus (ZIKV) is an arthropod-borne enveloped virus belonging to the Flavivirus genus in the family Flaviviridae, which also includes the human pathogenic yellow fever, dengue, West Nile and tick-borne encephalitis viruses 1 . Flaviviruses have two structural glycoproteins, prM and E (for precursor membrane and envelope proteins, respectively), which form a heterodimer in the endoplasmic reticulum (ER) of the infected cell and drive the budding of spiky immature virions into the ER lumen. These particles transit through the cellular secretory pathway, during which the trans-Golgi-resident protease furin cleaves prM. This processing is required for infectivity, and results in the loss of a large fragment of prM and reorganization of E on the virion surface. The mature particles have a smooth aspect, with 90 E dimers organized with icosahedral symmetry in a 'herringbone' pattern 2,3 .Three-dimensional cryo-electron microscopy (cryo-EM) structures of the mature ZIKV particles have recently been reported to near atomic resolution (3.8 Å) 4,5 , showing that the virus has essentially the same organization as the other flaviviruses of known structure, such as dengue virus (DENV) 3 and West Nile virus 6,7 . The E protein is about 500 amino acids long, with the 400 N-terminal residues forming the ectodomain essentially folded as β-sheets with three domains, named I, II and III, aligned in a row with domain I at the centre. The conserved fusion loop is at the distal end of the rod in domain II, buried at the E dimer interface. At the C terminus, the E ectodomain is followed by the 'stem' , featuring two α-helices lying flat on the viral membrane (the stem helices), which link to two C-terminal transmembrane α-helices. The main distinguishing feature of the ZIKV virion is an insertion within a glycosylated loop of E (the '150' loop), which protrudes from the mature virion surface 4,5 .Flaviviruses have been grouped into serocomplexes based on cross-neutralization studies with polyclonal immune sera 8 . The E protein is the main target of neutralizing antibodies, and is also the viral fusogen; cleavage of prM allows E to respond to the endosomal pH by undergoing a large-scale conformational change that catalyses membrane fusion and releases the viral genome into the cyotosol. Loss of the precursor fragment of prM lets the E protein fluctuate from its tight packing at the surface of the virion, transiently exposing otherwise buried surfaces. One surface exposed by this 'breathing' is the fusionloop epitope (FLE), which is a dominant cross-reactive antigenic site 9 . Although antibodies to this site can protect by complement-mediated mechanisms, as shown in a mouse model for West Nile virus 10 , they are poorly neutralizing and lead to antibody-dependent enhancement 11-15 , thereby aggravating Flavivirus pathogenesis and complicating the development of safe and effective vaccines.We recently reported the functional and structural characterization of a panel of antibodies isolated from patients with dengue disease 13,16 . ...

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination?

“…Interestingly, the FLE is highly conserved between DENVs and ZIKV and anti-FLE produced from DENV infected patients can bind with high affinity to monomeric ZIKV E-protein 21,22 . However, these anti-FLE mAb fail to neutralize ZIKV infection but promote ADE, which is consistent with the concept that ZIKV is more rigid than the DENVs thereby limiting access to the FLE 16,21,23 .…”

“…Crystal structures of EDE1 antibodies binding to the ZIKV envelope dimer reveal the strong conservation of this epitope between ZIKV and DENV 23 .…”

“…These mAb show substantial crossreaction between DENV and ZIKV suggesting that ZIKV could be considered as a fifth member of the DENV serocomplex. Interestingly, antibodies generated from DENV infected donors which are directed to the FLE, which can neutralize DENV, bind strongly to recombinant ZIKV envelope protein, but show poor neutralization of ZIKV yet still potently promote ADE of ZIKV infection 21,23,41 . This may be due to differences in breathing of the DENV and ZIKV virions as described above 16 .…”

Chimeric Pneumoviridae fusion proteins as immunogens to induce cross‐neutralizing antibody responses

“…In some cases, such as influenza virus (Kanekiyo et al , 2013; Krammer & Palese, 2014; Yassine et al , 2015) or human immunodeficiency virus (HIV) (Kwong et al , 2013), a universal vaccine is sought to overcome strain variability so that a single immunogen designed to reorient the antibody response toward relatively conserved antigenic regions would protect against infections with highly divergent antigenic variants. In other cases, the aim is to develop vaccines that will cross‐protect against related viruses from the same family, such as the Flaviviridae Zika and dengue viruses (Barba‐Spaeth et al , 2016). Beyond viruses, universal vaccines are also being designed for Neisseria meningitidis with chimeric variants of the factor H binding protein that incorporate epitopes of highly divergent bacterial strains (Scarselli et al , 2011).…”

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

“…E protein is a glycoprotein responsible for virus entry, representing a major target of neutralizing antibodies for Flaviviruses, including Zika virus, Dengue virus, and other mosquito-transmitted viruses from the same family, was shown to bind to DC-SIGN via the glycans on E proteins of the mature virion [70]. It has been already demonstrated that broadly neutralizing antibodies for E-dimer epitope isolated from patients with Dengue disease neutralize Zika as potently as they neutralize Dengue virus [71] E protein of Zika virus differs from the other known Flaviviruses in the ~10 amino acids that surround the Asn154 glycosylation site in the virus shell [68]. The virus projects a glycosylation site outward and glycans are attached to the viral protein surface at this site.…”