On the benefits of sin
Bibliographic record
Abstract
Antibodies (Abs) induced during infections with immunodeficiency viruses are subject to a form of original antigenic sin, termed repertoire freeze. This phenomenon encompasses conditions in which antigen (Ag)-specific B-cells and free Ab induced against early viral variants recognize viral escape mutants sufficiently to compete for Ag with naïve B-cells. As previously activated Ag-specific Abs and B-cells are more abundant than their naïve counterparts, they out-compete naïve B-cells and can be selected to undergo repeated rounds of somatic hypermutation and affinity maturation that drive repeated rounds of immune selection and viral escape. This situation prevents or diminishes the ability of B-cells carrying novel Ab-specificities to become activated and produce free Ab, facilitating viral escape. The enactment of repertoire freeze is illustrated in several features of anti-HIV antibodies, including persistently skewed κ/λ light chain ratios, preferential variable region gene usage, and the accumulation of Abs with extensive mutations within their variable regions. Furthermore, several investigators documented the presence of anti-viral Abs carrying a common idiotype, designated 1F7, from early infection onwards. In fact, anti-idiotypic suppression of these Abs in SHIV-infected rhesus macaques allowed the development of Abs that more effectively neutralized autologous contemporaneous viruses. Although most research suggests that repertoire freeze is undesirable for controlling an active infection, recent evidence has demonstrated that potentially protective broadly neutralizing Abs (BnAbs) develop within the freeze susceptible 1F7-idiotypic repertoire. This observation suggests that repeated rounds of selection of 1F7-idiotypic Abs may drive the extensive variable region mutation that characterizes BnAbs. In this review, we address how the demonstrated overlap between 1F7-idiotypic repertoire freeze and potentially protective Ab responses can be unravelled to generate novel vaccine concepts. Furthermore, we address how idiotypic regulation of the humoral immune response could be useful for sustaining protective Ab responses.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.002 | 0.003 |
| Scholarly communication | 0.003 | 0.003 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.028 | 0.004 |
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".