Abstract
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-targetingantibodies, CAP256-VRC26.25 (named for donor-lineage.clone and referred to hereafter as VRC26.25). Here, we determine the cryoelectron microscopy structure at 3.7Å 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.
Highlights
The first (V1) and second (V2) variable regions of the HIV-1 envelope (Env) are among the most sequence-variable regions of HIV-1 (Foley et al, 2018)
To provide a framework for understanding antibody recognition, we have used a class-based system of categorization in which members of the same antibody class have the same mode of recognition and similar B cell ontogeny (Kwong and Mascola, 2012, 2018)
Cryo-electron microscopy (EM) Structure of CAP256 Week 34 Env Trimer Bound by VRC26.25 Fab To determine the structure of VRC26.25 in complex with the Env trimer, we first sought to prepare a stable soluble trimer from the viral strain that originated the VRC26 lineage
Summary
The first (V1) and second (V2) variable regions of the HIV-1 envelope (Env) are among the most sequence-variable regions of HIV-1 (Foley et al, 2018). On the assembled prefusion-closed HIV-1 Env trimer, three sets of V1 and V2 loops surround a conserved apex, which is covered by a dense array of N-linked glycans (Lee et al, 2016; Stewart-Jones et al, 2016). Despite both sequence-variable regions and glycan shielding, the serological mapping of HIV-1-infected donors indicates the V1V2 apex to be commonly targeted by broadly neutralizing antibodies (Georgiev et al, 2013; Landais et al, 2016; Walker et al, 2010). The PGT145 class uses an extended CDR H3 to insert sulfated tyrosines into the hole at the V1V2 apex coincident with the trimer 3-fold axis (Lee et al, 2017; Liu et al, 2017; Rantalainen et al, 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
