Mechanisms of resistance associated with excision of incorporated nucleotide analogue inhibitors of HIV-1 reverse transcriptase
Bibliographic record
Abstract
PURPOSE OF REVIEW: Nucleoside analogue reverse transcriptase inhibitors are important components in current drug regimens used to treat infection with HIV. Despite the potency of drug combinations that involve two nucleoside reverse transcriptase inhibitors and a non-nucleoside analogue or a protease inhibitor, the emergence of resistance remains a major reason for treatment failure. This article reviews biochemical mechanisms associated with resistance to nucleoside reverse transcriptase inhibitors. RECENT FINDINGS: The thymidine analogues zidovudine and stavudine select for mutational patterns that facilitate the phosphorolytic excision of literally all available nucleoside reverse transcriptase inhibitors. Major progress has been made in defining genotypes that either support or counteract the reaction. Thymidine analogue-associated mutations were shown to increase rates of excision. In contrast, non-thymidine analogue reverse transcriptase inhibitors select for different mutations, e.g. M184V, L74V, and K65R that diminish the effects of thymidine analogue-associated mutations. Possible underlying biochemical mechanisms are discussed in this review. SUMMARY: The non-thymidine analogue-associated mutations M184V, L74V, and K65R show incompatibilities with thymidine-analogue-associated mutations. Maximizing these effects in clinical practice may help delay the emergence of resistance. Together, the clinical and biochemical data validate the excision reaction as a target for the development of novel compounds that interfere with the reaction.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".