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Virus glycoprotein nanodisc assembly platform for vaccine design

ABSTRACT: Transmembrane glycoproteins of enveloped viruses play a critical role in initiating infection by binding to host cell receptors and mediating viral entry. These proteins are essential targets for vaccine development as antibodies elicited by natural infection or immunization can bind to and prevent the virus entry. mRNA-LNP technology now allows in situ production of transmembrane glycoproteins upon immunization, but biophysical characterization of novel immunogens and in vitro analysis of antibody responses post-immunization rely largely on soluble proteins. These are typically obtained by truncation of membrane-proximal, transmembrane, and intracellular domains. Here, we present a methodological platform for assembling transmembrane virus glycoprotein vaccine candidates into lipid nanodiscs. The platform enables the use of transmembrane glycoproteins in analytical methods traditionally employed for soluble immunogens. We demonstrate the utility of the assembled glycoprotein nanodiscs in HIV MPER-targeting vaccine development by performing kinetic binding assays using SPR, ex vivo B cell sorting with FACS, and by resolving the structure of a prototypical HIV MPER targeting immunogen nanodisc in complex with three neutralizing antibodies, including MPER targeting antibody 10E8 to 3.6 Angstrom. Overall, the platform offers a valuable tool for accelerating the rational design and optimization of next-generation viral vaccines.

INSTRUMENT(S): Orbitrap Eclipse, Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: John R. Yates III

PROVIDER: MSV000098124 | MassIVE | Wed Jun 11 10:14:00 GMT+01:00 2025

SECONDARY ACCESSION(S): PXD064888

REPOSITORIES: MassIVE

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