Mutations in the E9L Polymerase Gene of Cidofovir-Resistant Vaccinia Virus Strain WR Are Associated with the Drug Resistance Phenotype
Bibliographic record
Abstract
Cidofovir (CDV) is an effective drug against viruses of the Orthopoxviridae family and is active in vitro against variola virus, the cause of smallpox. However, CDV-resistant poxviruses can be generated by repeated in vitro passage in the presence of suboptimal concentrations of CDV. To determine if mutations in the E9L polymerase gene could confer resistance to this nucleoside analog, this gene was sequenced from CDV-resistant vaccinia virus and found to encode five amino acid changes, centered on an N-terminal region associated with 3'-->5' exonuclease activity. Transfer of this mutant E9L gene into wild-type vaccinia virus by marker rescue sufficed to confer the resistance phenotype. E9L polymerase mutations occurred sequentially during passage in CDV, and an H296Y/S338F double mutant that conferred an intermediate CDV resistance phenotype was identified. In vitro, the marker-rescued CDV-resistant vaccinia virus containing all five mutations grew nearly as well as wild-type vaccinia virus. However, the virulence of this virus for mice was reduced, as 10- to 30-fold more CDV-resistant virus than wild-type virus was required for lethality following intranasal challenge. Cidofovir and hexadecyloxypropyl-cidofovir gave partial protection to mice infected with the virus when used at 50 and 100 mg/kg of body weight given as single treatments 24 h after virus exposure, whereas 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) was completely protective at 25, 50, and 100 mg/kg/day when given daily for 5 days. These findings suggest that drug therapy for poxviruses may be complicated by drug resistance but that treatment of the infection with currently known compounds is possible.
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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 | 0.001 |
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".