1. Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies.
- Author
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Henderson R, Anasti K, Manne K, Stalls V, Saunders C, Bililign Y, Williams A, Bubphamala P, Montani M, Kachhap S, Li J, Jaing C, Newman A, Cain DW, Lu X, Venkatayogi S, Berry M, Wagh K, Korber B, Saunders KO, Tian M, Alt F, Wiehe K, Acharya P, Alam SM, and Haynes BF
- Subjects
- Humans, HIV Infections immunology, HIV Infections virology, HIV Infections prevention & control, Broadly Neutralizing Antibodies immunology, Broadly Neutralizing Antibodies genetics, B-Lymphocytes immunology, Antibody Affinity immunology, Protein Engineering methods, HIV-1 immunology, HIV-1 genetics, Mutation, HIV Antibodies immunology, AIDS Vaccines immunology, AIDS Vaccines genetics, env Gene Products, Human Immunodeficiency Virus immunology, env Gene Products, Human Immunodeficiency Virus genetics, Molecular Dynamics Simulation, Antibodies, Neutralizing immunology
- 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., (© 2024. The Author(s).)
- Published
- 2024
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