Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines

Abstract

Enveloped viruses enter cells by inducing fusion of viral and cellular membranes, a process catalyzed by a specialized membrane-fusion protein expressed on their surface. This review focuses on recent structural studies of viral fusion proteins with an emphasis on their metastable prefusion form and on interactions with neutralizing antibodies. The fusion glycoproteins have been difficult to study because they are present in a labile, metastable form at the surface of infectious virions. Such metastability is a functional requirement, allowing these proteins to refold into a lower energy conformation while transferring the difference in energy to catalyze the membrane fusion reaction. Structural studies have shown that stable immunogens presenting the same antigenic sites as the labile wild-type proteins efficiently elicit potently neutralizing antibodies, providing a framework with which to engineer the antigens for stability, as well as identifying key vulnerability sites that can be used in next-generation subunit vaccine design.

The human coronavirus HCoV-229E S-protein structure and receptor binding

“…As we now show, this hydrophilic character is shared among the other coronavirus S-proteins for which structures exist (Figure 7c,d, Figure 7-figure supplement 1), an observation suggesting a conserved functional role. The coronavirus S2 subunit is large and the conformational changes on conversion to the post-fusion are more extensive than that shown by many other viral fusion proteins (Harrison, 2015;Rey and Lok, 2018). The HR1 triple helical coiled-coil, for example, is generated entirely on conversion to the post-fusion form.…”

X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications

“…The X-ray structures of a number of class I fusion proteins from different viral families have been determined in both pre-and post-fusion forms (reviewed in Ref. [14]), and the breaks in the Nhelix in the spring-loaded form have been mapped. In several of these structures, including filoviral GP, the break points were found downstream of a special turn in the N-helix that makes a "stutter" in the central coiled-coil.…”

“…The Env protein of all retroviruses infecting vertebrates is a class I viral fusion protein, a class that also includes the fusion glycoproteins (GPs) of the otherwise unrelated influenza viruses, coronaviruses, paramyxoviruses, pneumoviruses, filoviruses, and arenaviruses [14]. Class I proteins are type 1 single-pass transmembrane proteins that fold in the endoplasmic reticulum of the infected cell as a precursor that in most cases trimerizes directly upon folding.…”

Fluorescent antibiotics, vomocytosis, vaccine candidates and the inflammasome

“…Work presented by the international invited speaker in this session, Professor Shee-Mei Lok, from the DUKE-NUS Medical School in Singapore, described the first structure of the Zika virus capsid protein, demonstrating a triangular network of capsid dimers, knowledge that will be paramount in development of successful Zika virus vaccine candidates. 10 The latest on the inflammasome…”

“…The strategies presented, including siRNA targeting viral genomes or single‐chain neutralising antibodies, mediated almost a complete loss of detectable Zika or dengue virus replication in the midgut and whole body of mosquitoes homozygous for the novel traits. Work presented by the international invited speaker in this session, Professor Shee‐Mei Lok, from the DUKE‐NUS Medical School in Singapore, described the first structure of the Zika virus capsid protein, demonstrating a triangular network of capsid dimers, knowledge that will be paramount in development of successful Zika virus vaccine candidates …”