Structural insight into the mechanism of neuraminidase inhibitor-resistant mutations in human-infecting H10N8 Influenza A virus
Bibliographic record
Abstract
Abstract The emergence of drug resistance in avian influenza virus (AIV) is a serious concern for public health. Neuraminidase (NA) isolated from a fatal case of avian-origin H10N8 influenza virus infection was found to carry a drug-resistant mutation, NA-Arg292Lys (291 in N8 numbering). In order to understand the full potential of H10N8 drug resistance, the virus was first passaged in the presence of the most commonly used neuraminidase inhibitors (NAIs), oseltamivir and zanamivir. As expected, the Arg292Lys substitution was detected after oseltamivir treatment, however a novel Val116Asp substitution (114 in N8 numbering) was selected by zanamivir treatment. Next generation sequencing (NGS) confirmed that the mutations arose early (after passages 1-3) and became dominant in the presence of the NAI inhibitors. Extensive crystallographic studies revealed that N8-Arg292Lys resistance results mainly from loss of interactions with the inhibitor carboxylate, while rotation of Glu276 was not impaired as observed in the N9-Arg292Lys, a group 2 NA structure. In the case of Val116Asp, the binding mode between oseltamivir and zanamivir is different. Asp151 forms stabilized hydrogen bond to guanidine group of zanamivir, which may compensate the resistance caused by Val116Asp. By contrast, the amino group of oseltamivir is too short to maintain this hydrogen bond, which result in resistant. Moreover, the oseltamivir-zanamivir hybrid inhibitor MS-257 displays higher effectiveness to Val116Asp than oseltamivir, which support this notion. Author Summary Aside from vaccination, NAIs are currently the only alternative for the clinical treatment and prophylaxis of influenza. Understanding the mechanisms of resistance is critical to guide in drug development. In this study, two drug-resistant NA substitutions, Val116Asp and Arg292Lys, were discovered from oseltamivir and zanamivir treatment of H10N8 virus. Crystal structural analyses revealed two distinct mechanisms of these two resistant mutations and provide the explanation for the difference in susceptibility of different NAIs. Zanamivir and laninamivir were more effective against the resistant variants than oseltamivir, and Arg292Lys results in more serious oseltamivir resistance in N9 than N8 subtype. This study is well-correlated to influenza pandemic/epidemic pre-warning, as the discovery of inhibitor resistant viruses will help for new drug preparedness.
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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 | 0.000 |
| 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".