Epitope-targeting strategy for a vaccine against human immunodeficiency virus type-1; peptide ligands for the broadly-neutralizing antibodies b12, 2F5 and 2G12
Bibliographic record
Abstract
The research presented here is part of an ongoing effort to develop an epitopetargeted vaccine against the Human Immunodeficiency Virus type 1. We have used phage-displayed peptide libraries, in conjunction with other biochemical and structural techniques, to generate and characterize peptides specific for the broadly-neutralizing, human monoclonal antibodies (Mab) b12,2F5 and 2G12. First, peptide ligands for Mab b12 were isolated. One peptide, B2.1, was characterized in detail. The crystal structure of B2.1 in complex with b12 Fab was solved and compared with a model of the antibody docked to gp120. B2.1 was used to immunize mice, seeking to generate a b12-like, neutralizing antibody response. Minimal structural resemblance between the putative b12 epitope and B2.1 peptide was observed, indicating different mechanisms of binding to b12. Moreover, the anti B2.1 response from the immunized mice did not cross-react with gp120, further indicating this difference. Second, we demonstrate that Mab 2F5, which binds to the sequence ELDKWA on gp41, selects peptides with multiple, different amino acid sequences flanking its threeresidues DKW native core epitope. High-affinity binding was achieved by peptides with unrelated flanking sequences C-terminal to the core epitope, with the nature and location of critical binding residues differing between peptides. Our results implicate multiple mechanisms of binding, and suggest the existence of two distinctive functional regions in the 2F5 paratope, one that is DKW-specific and one that is multi-specific. Finally, a peptide ligand specific for the carbohydrate-binding Mab 2G12 was isolated, characterized and optimized. The peptide competes with carbohydrate ligands for binding to 2G12. The crystal structure of the 2G12-peptide complex, and its comparison with the 2G 1 2-Man9GlcNAc2 complex, shows that the peptide is not a mimic of Man9GlcNAc2. They occupy separate sites in the antibody's paratope, with minimal overlaping, therefore the peptide and Man,GlcNAc, make a different set of contacts with the Mab. In summary, we have observed that peptide mimicry of the b12,2F5 and 2G12 epitopes is essentially functional, not structural. Our results indicate that these ligands can be used as antibody-specific markers, and that most likely, conventional immunizations with so-called peptide mimics will not elicit these antibodies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".