Jason Gorman, Reid B Ballard, Alexandra F Nazzari, Sijy O'Dell, Tatsiana Bylund, Reda Rawi, Renguang Du, Richard Nguyen, David Ambrozak, Baoshan Zhang, Haijuan Du, Nicole A Doria-Rose, Mark Connors, John R Mascola, Tongqing Zhou, Peter D Kwong, Mario Roederer, Rosemarie D Mason
Many HIV-1 broadly neutralizing antibodies (bnAbs) account for envelope (Env) glycan shielding by supplementing antibody-protein interactions with antibody-glycan interactions. Further, bnAbs that interact predominantly via glycans can augment their binding through antigen-binding fragment (Fab) dimerization, generally utilizing non-variable region interactions. Here, we examined a donor whose serum identified glycan-reactivity (antibody 2G12-like) and CD4 binding-site (CD4bs) reactivity and isolated both glycan-reactive and CD4bs-reactive antibodies. The CD4bs antibodies were members of the VRC01-antibody class and neutralized nearly 70% of HIV-1 (208-strain panel). The glycan-reactive antibody had ∼30% breadth, and cryo-EM analysis revealed it to be a Fab-dimerized glycan (FDG)-reactive antibody with a distinct architecture wherein the Fab arms dimerized through a disulfide bond at the tips of the complementarity-determining loops that wedged between two glycans. Overall, we identified an FDG antibody that recognized through a "dual-glycan clamp" epitope and is the second FDG antibody to be isolated from an HIV-infected donor since antibody 2G12.