Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility

Kemin Tan, Junjian Chen, Yu Kaku, Yi Wang, Luke Donius, Rafiq Ahmad Khan, Xiaolong Li, Hannah Richter, Michael S. Seaman, Thomas Walz, Wonmuk Hwang, Ellis L. Reinherz () and Mikyung Kim ()
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Kemin Tan: Argonne National Laboratory
Junjian Chen: Dana-Farber Cancer Institute
Yu Kaku: Dana-Farber Cancer Institute
Yi Wang: Dana-Farber Cancer Institute
Luke Donius: Dana-Farber Cancer Institute
Rafiq Ahmad Khan: Dana-Farber Cancer Institute
Xiaolong Li: Dana-Farber Cancer Institute
Hannah Richter: Beth Israel Deaconess Medical Center
Michael S. Seaman: Beth Israel Deaconess Medical Center
Thomas Walz: The Rockefeller University
Wonmuk Hwang: Texas A&M University
Ellis L. Reinherz: Dana-Farber Cancer Institute
Mikyung Kim: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Broadly neutralizing antibodies (bnAbs) against HIV-1 target conserved envelope (Env) epitopes to block viral replication. Here, using structural analyses, we provide evidence to explain why a vaccine targeting the membrane-proximal external region (MPER) of HIV-1 elicits antibodies with human bnAb-like paratopes paradoxically unable to bind HIV-1. Unlike in natural infection, vaccination with MPER/liposomes lacks a necessary structure-based constraint to select for antibodies with an adequate approach angle. Consequently, the resulting Abs cannot physically access the MPER crawlspace on the virion surface. By studying naturally arising Abs, we further reveal that flexibility of the human IgG3 hinge mitigates the epitope inaccessibility and additionally facilitates Env spike protein crosslinking. Our results suggest that generation of IgG3 subtype class-switched B cells is a strategy for anti-MPER bnAb induction. Moreover, the findings illustrate the need to incorporate topological features of the target epitope in immunogen design.

Date: 2023
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DOI: 10.1038/s41467-023-42097-6

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