SummaryRecent efforts toward HIV vaccine development include the design of immunogens that can engage B cell receptors with the potential to affinity mature into broadly neutralizing antibodies (bnAbs). V2-apex bnAbs, which bind a protein-glycan region on HIV envelope glycoprotein (Env) trimer, are among the most broad and potent described. We show here that a rare “glycan hole” at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bnAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, we immunized wild-type rabbits with soluble trimers adapted from these Envs. Potent autologous tier 2 neutralizing responses targeting basic residues in strand C of the V2 region, which forms the core epitope for V2-apex bnAbs, were observed. Neutralizing monoclonal antibodies (mAbs) derived from these animals display features promising for subsequent broadening of the response.
40Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly 41 neutralizing antibody (bnAb) sites by sequential immunization. Chimpanzee SIV 42 Envelope (Env) shares a single bnAb site, the V2-apex, with HIV, suggesting its 43 possible utility in an HIV immunization strategy. Accordingly, we generated a 44 chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-45 apex bnAbs and precursor versions, but no binding to other HIV specificities. We 46 determined the structure of the MT145K trimer by cryo-EM and showed its 47 architecture was remarkably similar to HIV Env. Immunization of an HIV V2-apex 48 bnAb precursor Ab-expressing knock-in mouse with chimpanzee MT145K trimer 49 induced HIV V2-specific neutralizing responses. Subsequent boosting with an HIV 50 trimer cocktail induced responses exhibiting some virus cross-neutralization. 51Overall, the chimpanzee MT145K trimer behaves as expected from design both in 52 vitro and in vivo and is an attractive potential component of a sequential 53 immunization regimen to induce V2-apex bnAbs. 54 55 2015; McGuire et al., 2016; Sok et al., 2016a; Steichen et al., 2016b; Tian et al., 77 2016; Williams et al., 2017). Thus, immunogen designs and strategies that can 78 select rare bnAb precursors and reduce off-target B cell responses are valuable 79 for nAb immunofocusing efforts. 80 81 One of the Env sites that has shown great promise for vaccine targeting is the V2 82 apex bnAb epitope (Andrabi et al., 2015; Gorman et al., 2016; Voss et al., 2017). 83This bnAb epitope sits at the 3-fold axis of the trimer and is primarily formed by a 84 patch rich in positively charged lysine residues and protected by two glycans at 85 HXB2 HIV-1 reference positions N160 and N156/N173 that are part of the Env 86 106 Of note, among the major HIV Env bnAb specificities that include V2-apex, V3-107 N332, CD4bs and gp120-41 interface, the V2 apex site is the only bnAb site that 108 consistently exhibits cross-group neutralizing activity with virus Envs derived from 109HIV-1 group M, N, O and P (Braibant et al., 2013; Morgand et al., 2016). In addition, 110 V2-apex bnAbs display cross-neutralizing activity with the Simian 111Immunodeficiency Virus (SIV) isolates that infect chimpanzees (SIVcpzPtt [Pan 112troglodytes troglodytes], SIVcpzPts [Pan troglodytes schweinfurthii]) and gorillas 113 (SIVgor) (Barbian et al., 2015). The retention of the V2 apex bnAb epitope at the 114 time of species cross-over from chimpanzees to humans highlights the biological 115 significance of this region and here we sought to design a trimer based on the 116 SIVcpzPtt Env sequence that could potentially guide an immunofocused response 117
Summary Apex broadly neutralizing HIV antibodies (bnAbs) recognize glycans and protein surface close to the 3-fold axis of the envelope (Env) trimer and are among the most potent and broad Abs described. The evolution of apex bnAbs from one donor (CAP256) has been studied in detail and many Abs at different stages of maturation have been described. Using diverse engineering tools, we investigated the involvement of glycan recognition in the development of the CAP256.VRC26 Ab lineage. We found that sialic acid-bearing glycans were recognized by germline-encoded and somatically mutated residues on the Ab heavy chain. This recognition provided an “anchor” for the Abs as the core protein epitope varies, prevented complete neutralization escape, and eventually led to broadening of the response. These findings illustrate how glycan-specific maturation enables a human Ab to cope with pathogen escape mechanisms and will aid in optimization of immunization strategies to induce V2 apex bnAb responses.
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