Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. Here, to precisely engineer bnAb boosting immunogens, we use molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identify Env mutations predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encode antibody affinity gains and select for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.

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Institutions

Publication Details

Journal
Nature Communications
Published
2024-11-03
DOI
https://doi.org/10.1038/s41467-024-53120-9
Citations
7
Primary Topic
HIV Research and Treatment
Type
article
Field-Weighted Citation Impact
2.06

Funders

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article

Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Priyamvada Acharya, Victoria Stalls, Ashliegh Williams, S. Munir Alam et al.
7 citations
Nature Communications
HIV Research and Treatment
2.06
article

Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Priyamvada Acharya, Victoria Stalls, Ashliegh Williams, S. Munir Alam, Bette Korber, Sangita Kachhap, Frederick W. Alt, Amanda Newman, Kartik Manne, Rory Henderson, Barton F. Haynes, Carrie Saunders, Yishak Bililign, Derek W. Cain, Kevin J. Wiehe, Maya Montani, Kevin O. Saunders, Kara Anasti, Sravani Venkatayogi, Kshitij Wagh, Pimthada Bubphamala, Jingjing Li, Xiaozhi Lu, Chuancang Jaing, Ming Tian, Madison Berry
article en
7 citations

Abstract

Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. Here, to precisely engineer bnAb boosting immunogens, we use molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identify Env mutations predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encode antibody affinity gains and select for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.

Nature CommunicationsVol. 15(1)
Boston Children's Hospital (US), Los Alamos National Laboratory (US), Harvard University (US), Duke University (US), New Mexico Consortium (US), Duke Medical Center (US), Duke University Hospital (US)
National Science Foundation, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Electrical, Communications and Cyber Systems
Good health and well-being
Openalex Percentile: Top 13%
HIV Research and Treatment
2.06
DOIOpen Access PDFOpenAlex
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