| Summary: | Summary: Antibodies targeting the V1V2 apex of the HIV-1 envelope (Env) trimer comprise one of the most commonly elicited categories of broadly neutralizing antibodies. Structures of these antibodies indicate diverse modes of Env recognition typified by antibodies of the PG9 class and the PGT145 class. The mode of recognition, however, has been unclear for the most potent of the V1V2 apex-targeting antibodies, CAP256-VRC26.25 (named for donor-lineage.clone and referred to hereafter as VRC26.25). Here, we determine the cryoelectron microscopy structure at 3.7 Å resolution of the antigen-binding fragment of VRC26.25 in complex with the Env trimer thought to have initiated the lineage. The 36-residue protruding loop of VRC26.25 displays recognition incorporating both strand-C interactions similar to the PG9 class and V1V2 apex insertion similar to the PGT145 class. Structural elements of separate antibody classes can thus intermingle to form a “combined” class, which in this case yields an antibody of extraordinary potency. : Antibody CAP256-VRC26.25 is one of the most potent known HIV-1-neutralizing antibodies. Gorman et al. determine the cryo-EM structure of this antibody in complex with the Env trimer that initiated the antibody lineage. The structure reveals how elements of distinct antibody classes can intermingle to yield an antibody of extraordinary potency. Keywords: broadly neutralizing antibody, HIV-1 envelope trimer, multidonor antibody class, PCT64, PG9, PGDM1400, PGT145, tyrosine sulfation, V1V2 apex recognition
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