Abstract
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.
Highlights
Neutralizing antibodies to HIV can protect against immunodeficiency viruses in animal models (Moldt et al, 2012; Pegu et al, 2014; Shingai et al, 2014), and their induction is seen as important for the generation of a successful HIV vaccine (Burton and Hangartner, 2016; Haynes and Mascola, 2017)
Despite these viral evasion strategies, broadly neutralizing antibodies can emerge after years of affinity maturation during natural HIV infection in some individuals. These bnAbs, their affinity maturation from naive precursors, and their binding to HIV envelope glycoprotein (Env) are being intensively studied in the hope that the information gathered can be used to design immunogens to elicit bnAbs, a process that has been termed ‘‘reverse vaccinology 2.0’’ (Burton, 2002, 2017; Rappuoli et al, 2016)
The V2-apex glycan hole is modeled onto the BG505 SOSIP structure (Gristick et al, 2016), in Figure 1B to reveal absent predicted N-linked glycosylation (PNG) sites at position 130 (HXB2 numbering) and within a loop projecting apically from the V2 hypervariable region designated V20 (HXB2 183–191)
Summary
Neutralizing antibodies to HIV can protect against immunodeficiency viruses in animal models (Moldt et al, 2012; Pegu et al, 2014; Shingai et al, 2014), and their induction is seen as important for the generation of a successful HIV vaccine (Burton and Hangartner, 2016; Haynes and Mascola, 2017). The antibody-accessible protein surfaces are highly variable in sequence and dynamic due to shifting N-linked glycan sequons, resulting in neutralizing responses that are mostly isolate specific (Moore et al, 2012; Sok et al, 2014). Despite these viral evasion strategies, broadly neutralizing antibodies (bnAbs) can emerge after years of affinity maturation during natural HIV infection in some individuals. These bnAbs, their affinity maturation from naive precursors, and their binding to HIV Env are being intensively studied in the hope that the information gathered can be used to design immunogens to elicit bnAbs, a process that has been termed ‘‘reverse vaccinology 2.0’’ (Burton, 2002, 2017; Rappuoli et al, 2016)
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