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bioRxiv · 10.64898/2025.12.17.694829

Structural determination of the HIV-1 Variable Region 3 epitope of antibody 19b

Fetics, S.·Mehta, A.·Nicely, N. I.·Chen, C.-H.·Lindenberger, J.·Acharya, P.
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Abstract

The HIV-1 Envelope (Env) in its pre-receptor "closed" conformation is targeted by broadly neutralizing antibodies (bnAbs), while its receptor-bound "open" conformation, exposes immunodominant epitopes targeted by non-neutralizing antibodies. A human immunoglobin G (IgG) monoclonal antibody (mAb), 19b, binds an Env third variable (V3) loop epitope that is only exposed in the open Env conformation. Despite widespread use of 19b to detect the open Env conformation in immunoassays, its epitope has not yet been structurally defined. Here we determine crystal structures of ligand-free and V3 peptide-bound 19b Fab to visualize details of this interaction. 19b utilizes both its heavy and light chains to interact with the V3 loop. The 5-residue heavy chain complementarity-determining region (CDR H3) facilitates a hydrophobic pocket for V3 residues to associate with. 19b adopts a cradle binding mode with its CDRH1, CDRL2 and CDRL3 mediating interactions with V3 regions that flank the conserved GPGR/Q motif, without making substantial contacts with the GPGR arch region. Our high-resolution structures by elucidating the epitope, binding mode and the structural basis for the broad reactivity of 19b, fill a gap in our knowledge of a reagent that is widely used in immunoassays.

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Fetics, S., Mehta, A., Nicely, N. I., Chen, C.-H., Lindenberger, J., Acharya, P.. 2025-12-17. Structural determination of the HIV-1 Variable Region 3 epitope of antibody 19b. https://doi.org/10.64898/2025.12.17.694829

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