Abstract
ABSTRACTBroadly neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER) in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc) regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively. Trimeric scaffolds were also identified to stabilize the MPER-containing BG505 gp140.681 trimer in a native-like conformation. Following structural and antigenic evaluation, a subset of scaffold and trimer antigens was selected for immunization in BALB/c mice. Serum binding revealed distinct patterns of antibody responses to these two bNAb targets presented in different structural contexts. For example, the N332 nanoparticles elicited glycan epitope-specific antibody responses that could also recognize the native trimer, while a scaffolded BG505 gp140.681 trimer generated a stronger and more rapid antibody response to the trimer apex than its parent gp140.664 trimer. Furthermore, next-generation sequencing (NGS) of mouse splenic B cells revealed expansion of antibody lineages with long heavy-chain complementarity-determining region 3 (HCDR3) loops upon activation by MPER scaffolds, in contrast to the steady repertoires primed by N332 nanoparticles and a soluble gp140.664 trimer. These findings will facilitate the future development of a coherent vaccination strategy that combines both epitope-focused and trimer-based approaches.
Highlights
Neutralizing antibodies have provided valuable insights into the humoral immune response to HIV-1
Structures of the N332 glycan-dependent broadly neutralizing antibodies (bNAbs) in complex with individual glycans, gp120 domains, and native-like gp140 trimers have provided important insights into how these bNAbs recognize a cluster of carbohydrates on gp120 and neutralize diverse HIV-1 isolates [23, 24, 51,52,53,54]
The crystal structure of bNAb PGT128 bound to an engineered gp120 outer domain with a truncated variable loop 3 (V3) loop established the N-linked glycans at positions N332 and N301, as well as the C-terminal V3 stem, as the primary antibody-binding sites [23]
Summary
Neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. Next-generation sequencing (NGS) of mouse splenic B cells revealed expansion of antibody lineages with long heavy-chain complementarity-determining region 3 (HCDR3) loops upon activation by MPER scaffolds, in contrast to the steady repertoires primed by N332 nanoparticles and a soluble gp140.664 trimer These findings will facilitate the future development of a coherent vaccination strategy that combines both epitope-focused and trimer-based approaches. IMPORTANCE Both epitope-focused and trimer-based strategies are currently being explored in HIV-1 vaccine development, which aims to elicit broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the viral envelope (Env). The presence of immunodominant but nonneutralizing epitopes, in addition to poor recognition of bNAb epitopes due to glycan masking and restricted angles of approach, has impeded vaccine development [11, 12] Both epitope-focused and trimer-based strategies are currently being explored for HIV-1 vaccine design. The lack of in vivo evaluation has hindered further development of these epitope scaffolds as immunogens
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