1098. How Morbilliviruses Antagonize Innate Immunity and Swiftly Inactivate the Adaptive Immune System
Bibliographic record
Abstract
INTRODUCTION. About 700,000 children die each year due to the consequences of measles-induced immunosuppression. The lack of a small animal model has limited studies of measles virus (MV) pathogenesis, but experimental infections of ferrets with canine distemper virus (CDV) recapitulate many immunosuppression hallmarks observed after MV infection: depression of tuberculin/DTH test responses, lowered leukocyte counts and antibody titers, and reduced in vitro lymphocyte proliferation activity. RESULTS. To analyze the viral determinants of immunosuppression we generated CDV either selectively receptor-blind or incapable of expressing either one, or both, candidate interferon antagonists proteins. Our analysis revealed striking similarities between the early phases of immunosuppression induced by morbilliviruses and HIV. A few days after inoculation, massive infection of primary and secondary lymphatic organs including intestinal Peyer's patches occurred depending on recognition of the signaling lymphocytic activation molecule (SLAM, CD150). Infection of about half the circulating lymphocytes, selective depletion of T-cells, and complete inhibition of the cytokine response followed. These events depend on V, the essential interferon antagonist and cytokine response inhibitor. An effect of the other viral protein C on the severity of rash and digestive symptoms was observed only in a V-defective genetic background. DISCUSSION. These findings reform our understanding of morbillivirus immunosuppression: we prove formally that SLAM is the primary morbillivirus receptor, that V is the essential interferon antagonist and cytokine response inhibitor, and that V is an infectivity factor. Understanding of the viral determinants of immunosuppression provides guidance for the development of measles virus-based multivalent vaccines and oncolytic vectors. INTRODUCTION. About 700,000 children die each year due to the consequences of measles-induced immunosuppression. The lack of a small animal model has limited studies of measles virus (MV) pathogenesis, but experimental infections of ferrets with canine distemper virus (CDV) recapitulate many immunosuppression hallmarks observed after MV infection: depression of tuberculin/DTH test responses, lowered leukocyte counts and antibody titers, and reduced in vitro lymphocyte proliferation activity. RESULTS. To analyze the viral determinants of immunosuppression we generated CDV either selectively receptor-blind or incapable of expressing either one, or both, candidate interferon antagonists proteins. Our analysis revealed striking similarities between the early phases of immunosuppression induced by morbilliviruses and HIV. A few days after inoculation, massive infection of primary and secondary lymphatic organs including intestinal Peyer's patches occurred depending on recognition of the signaling lymphocytic activation molecule (SLAM, CD150). Infection of about half the circulating lymphocytes, selective depletion of T-cells, and complete inhibition of the cytokine response followed. These events depend on V, the essential interferon antagonist and cytokine response inhibitor. An effect of the other viral protein C on the severity of rash and digestive symptoms was observed only in a V-defective genetic background. DISCUSSION. These findings reform our understanding of morbillivirus immunosuppression: we prove formally that SLAM is the primary morbillivirus receptor, that V is the essential interferon antagonist and cytokine response inhibitor, and that V is an infectivity factor. Understanding of the viral determinants of immunosuppression provides guidance for the development of measles virus-based multivalent vaccines and oncolytic vectors.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".