Structure-guided vaccination elicits broadly neutralizing antibodies targeting the HIV-1 silent face
Year: 2026
Type: preprint
Abstract: ABSTRACT An effective HIV-1 vaccine will likely require broadly neutralizing antibodies (bnAbs) targeting multiple complementary epitopes on the Envelope (Env) glycoprotein. Donor-derived bnAbs targeting the conserved silent face (SF) epitope complement established bnAb classes, but the maturation pathways underlying SF bnAb development and their inducibility via vaccination remain poorly understood. Here, we elicit SF-like bnAbs by vaccination and define pathways by which these responses can be guided toward breadth. Structural analysis of the donor-derived bnAb SF10 revealed that broad neutralization depends on a minimal set of heavy chain mutations despite extensive overall somatic hypermutation. We leveraged these insights to engineer Env immunogens that engage an SF10 precursor and selectively favor breadth-associated mutations during sequential immunization in a new immunoglobulin knock-in mouse model. Vaccination reproducibly elicited heterologous neutralizing serum responses and monoclonal antibodies that acquired key SF-like improbable mutations and broad neutralizing activity. Notably, elicited antibodies combined features of distinct human SF bnAbs, demonstrating that vaccination can access alternative mutational solutions rather than precisely recapitulating a donor-derived maturation pathway. These findings establish the silent face as a tractable vaccine target and expand the bnAb specificities available for multi-epitope HIV-1 vaccine strategies.
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, U.S. Department of Energy, Bill and Melinda Gates Foundation, California Institute of Technology, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1229526393, G1286251239, G2371548206, G262532246, G303061748, G315621713, Duke University - to facilitate the discovery and licensure of a safe, effective and practical HIV vaccine, or long-acting biologic intervention, to prevent the acqu..., G4202012489, G4235786860, G4581610328, G495301720, G498139845, G5570207115, Wistar Institute of Anatomy & Biology - to generate model systems to accelerate HIV vaccine design, G6550344761, Stanford University - to explore novel ways to elicit neutralizing antibodies against HIV-1 in pre-clinical models, G7283024673, G7396808078, G7863156295, G8207748872, G8382000481, G8925327636, A Synchrotron Radiation Structural Biology Resource, G911061179
OpenAlex ID: W7218957815