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| Title | Decoding epitope immunodominance in HIV Env using cryoEM and machine learning. |
|---|---|
| Journal, issue, pages | bioRxiv, Year 2026 |
| Publish date | Mar 11, 2026 |
Authors | Jan S Schuhmacher / Shuhao Xiao / Elise R Eray / Sharidan Brown / Alexander Zambrowski / Aryan Jain / Daniel Montiel Garcia / Gabriel Ozorowski / Wenwen Zhu / Katrina Saam / Tom G Caniels / John P Moore / Max Crispin / Rogier W Sanders / Srirupa Chakraborty / Bruno E Correia / Andrew B Ward / Aleksandar Antanasijevic / ![]() |
| PubMed Abstract | Viral surface glycoproteins, such as the HIV envelope protein (Env), present numerous antibody (Ab) epitopes, yet immune responses consistently focus on only a subset, a phenomenon known as ...Viral surface glycoproteins, such as the HIV envelope protein (Env), present numerous antibody (Ab) epitopes, yet immune responses consistently focus on only a subset, a phenomenon known as immunodominance. Although structural studies have provided insights into Env antigenicity, our understanding of the molecular features that govern efficient Ab engagement remains incomplete, thereby limiting the predictive and rational design of vaccines. Here, we characterized the structural determinants of epitope immunodominance in HIV Env by integrating high-resolution cryoEM-based polyclonal epitope mapping (cryoEMPEM) across different clades with quantitative analyses of epitope topology, accessibility, and physicochemical properties. More than 70 new structures were resolved to assemble a library of >100 Env-antibody complexes. These data informed the development of a surface-centric, machine-learning model to predict relative ntigen urface mmunodominance (ASI model). Comparison of ASI-predicted epitope sites with the specificities of Env-induced antibodies showed that the model accurately identifies immunodominant regions and highlights the structural features driving immune bias. Notably, immunogens redesigned based on model predictions successfully redirected Ab responses toward a normally subdominant epitope, demonstrating the potential of strategies coupling targeted assembly of focused structural libraries with machine learning to uncover complex molecular patterns and enable design of more effective vaccine antigens. |
External links | bioRxiv / PubMed:41959402 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 20.0 Å |
| Structure data | ![]() EMDB-56907: Polyclonal immune complex comprising AMC009 SOSIP.v4.2 in complex with polyclonal antibodies from rabbit UA0062 - Obtained by negative stain EM. ![]() EMDB-56914: Polyclonal immune complex comprising AMC009 SOSIP.v4.2 in complex with polyclonal antibodies from rabbit UA0063 - Obtained by negative stain EM. ![]() EMDB-56922: Polyclonal immune complex comprising AMC009 SOSIP.v4.2 in complex with polyclonal antibodies from rabbit UA0065 - Obtained by negative stain EM. ![]() EMDB-56923: Polyclonal immune complex comprising AMC009 SOSIP.v4.2 in complex with polyclonal antibodies from rabbit UA0064 - Obtained by negative stain EM. ![]() EMDB-56924: Polyclonal immune complex comprising AMC009 SOSIP.v4.2 in complex with polyclonal antibodies from rabbit UA0066 - Obtained by negative stain EM. ![]() EMDB-56925: Polyclonal immune complex comprising B41 SOSIP.v4.1 in complex with polyclonal antibodies from rabbit r1644 - Obtained by negative stain EM. ![]() EMDB-56927: Polyclonal immune complex comprising B41 SOSIP.v4.1 in complex with polyclonal antibodies from rabbit r1645 - Obtained by negative stain EM. ![]() EMDB-56935: Polyclonal immune complex comprising B41 SOSIP.v4.1 in complex with polyclonal antibodies from rabbit r1648 - Obtained by negative stain EM. ![]() EMDB-56940: Polyclonal immune complex comprising CH505(B) SOSIP.v8.1 in complex with polyclonal antibodies from rabbit r2473 - Obtained by negative stain EM. ![]() EMDB-56941: Polyclonal immune complex comprising CH505(B) SOSIP.v8.1 in complex with polyclonal antibodies from rabbit r2475 - Obtained by negative stain EM. ![]() EMDB-56942: Polyclonal immune complex comprising CH505(B) SOSIP.v8.1 in complex with polyclonal antibodies from rabbit r2476 - Obtained by negative stain EM. ![]() EMDB-56943: Polyclonal immune complex comprising CH505(B) SOSIP.v8.1 in complex with polyclonal antibodies from rabbit r2477 - Obtained by negative stain EM. |
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Human immunodeficiency virus 1