Cross‐Neutralizing and Broadly Neutralizing Human Antibodies Against Nonenveloped Viruses

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  FIGURE 1. Neutralization mechanisms targeting nonenveloped viruses. Nonenveloped vertebrate viruses possess metastable icosahedral capsids organized around two‐, three‐, and fivefold symmetry axes. Before cell entry, neutralizing antibodies act through three major extracellular mechanisms: (A) virion aggregation [71], (B) blockade of receptor or co‐receptor engagement by targeting exposed functional domains or transiently accessible cryptic epitopes, including through steric hindrance around symmetry axes [12, 72, 73, 74], and (C) premature capsid disassembly driven by capsid metastability, either via receptor‐mimicking interactions that induce early uncoating and genome release, or via physical collision effects that separate neighboring capsomeres, leading to capsid deformation and collapse [19, 42, 62, 63, 75, 76, 77]. Intracellular neutralization mechanisms include (D) inhibition of viral uncoating through capsid stabilization or antibody binding to cryptic epitopes exposed upon capsid rearrangements [12, 78], and (E) cytosolic neutralization mediated by the Fc receptor TRIM21, which promotes ubiquitin‐dependent proteasomal degradation of antibody–virus complexes [60, 64, 79]. Figure…

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  FIGURE 2. Surface representations of the capsids of different nonenveloped viruses. The region enlarged in each panel is indicated by a pink dashed box and labeled in pink. Enlarged views show the corresponding capsid oligomer (pentamer or dimer). For dimers, the two monomers are colored gray and lavender. Antibody epitopes are highlighted in the indicated colors, whereas the interaction footprints of known cellular receptors are outlined with solid lines. (A) AAV9 (PDB: 7WJW). Antibodies: MAb1–6 (blue; PDB: 9B6S) and mAb2–7 (red; PDB: 9B7Q). Cellular receptor: AAVR PKD2 (black line; PDB: 6JCQ). (B) Hepatitis E virus (PDB: 2ZTN). Antibodies: ES1.327 (blue; PDB: 9FNS), ES4.431 (purple; PDB: 9FNT), p60.12 (red; PDB: 8PMX), and p60.1 (orange; PDB: 8PMW). No cellular receptor has been identified. (C) Poliovirus (PDB: 1VBD). Antibody: 9H2 (light pink; PDB: 8E8Z). Cellular receptor: CD155/PVR (black line; PDB: 3EPC). (D) Enterovirus D68 (PDB: 9MXC). Antibody: EV68‐228 (blue; PDB: 6WDT). Cellular receptors: Sialic acid (black line; PDB: 5BNP) and Fc‐MFSD2A (pink line; PDB: 9MXC). (E) Norovirus (PDB: 7MRY). GII.4: Antibodies NORO‐320 (red; PDB: 7JIE) and VX22 (purple; PDB: 8VKX); cellular…