Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

Abstract Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2 and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely viral fusion glycoproteins....

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Bibliographic Details
Published in:bioRxiv 2021-02
Main Authors: Turner, Hannah L, Andrabi, Raiees, Cottrell, Christopher A, Richey, Sara T, Song, Ge, Callaghan, Sean, Anzanello, Fabio, Moyer, Tyson J, Wuhbet Abraham, Melo, Mariane, Silva, Murillo, Scaringi, Nicole, Rakasz, Eva G, Sattentau, Quentin, Irvine, Darrell J, Burton, Dennis R, Ward, Andrew B
Format: Article
Language:English
Subjects:
Antibodies
Electron microscopy
Epitope mapping
Glycoproteins
HIV
Human immunodeficiency virus
Immunization
Influenza
Severe acute respiratory syndrome coronavirus 2
Trimers
Vaccines
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Summary:Abstract Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2 and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non or weakly neutralizing (“off-target”) antibodies. Using our recently developed electron microscopy epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵# Lead Contact * Teaser Statement: HIV Env trimers elicit antibodies that lead to their own destruction
DOI:10.1101/2021.02.16.431310