Acquired resistance to reoviral oncolysis
Bibliographic record
Abstract
3381 The naturally occurring human reovirus has shown considerable potential as an oncolytic agent for Ras-dependent tumor cells in vitro and in animal model systems and is currently in human clinical trials. However, the potential for virus-susceptible tumor cell lines that contain activating mutations of Ras to develop resistance to reovirus has not been fully explored. To address this, we exposed the human fibrosarcoma HT1080 cell line, which contains an activated N-Ras gene and is highly sensitive to viral oncolysis, to several rounds of exposure to reovirus. Most but not all cells were killed on first exposure, and after three rounds of selection we derived populations that were highly resistant to viral oncolysis. The resistant cells were persistently infected by reovirus, producing functional reovirus continuously. The resistant cells retained the activating N-Ras mutation and high levels of Ras activity, suggesting that reduced Ras activity is not required for viral resistance. Reovirus generated from the resistant cells contains several mutations and shows reduced but still significant apoptotic potential in HT1080 cells compared to wild type reovirus. In addition, virus-resistant cells showed reduced cellular cathepsin B activity, which is associated with the viral infection cycle. The persistently infected cells can be cured of virus by growth in the presence of reovirus antibody for 3 weeks, generating virus-free ‘cured’ cells. The persistently infected cells and cured cells were then tested for tumor formation in SCID mice. In sharp contrast to the highly tumorigenic parental and cured cells, the persistently infected cells were not tumorigenic in vivo. Furthermore, the persistently infected cells were able to suppress the cured cells’ tumorigenic activity when co-injected, suggesting that reoviral persistence plays an important role in tumor suppression. To determine whether the reovirus-resistant cells can still be killed by chemotherapeutic agents or other oncolytic viruses, we challenged them with apoptotic inducers and E1B-negative adenovirus, resulting in significant apoptosis following both approaches. These findings suggest that both reovirus and host tumor cells can co-adapt during the acquisition of viral resistance. Even so, the virus-resistant tumor cells can still be killed by other anti-tumor strategies, and have not lost the capacity for apoptosis.
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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) | 0.002 | 0.001 |
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".