Targeting of the Purine Biosynthesis Host Cell Pathway Enhances the Activity of Tenofovir Against Sensitive and Drug-Resistant HIV-1
Bibliographic record
Abstract
BACKGROUND: Targeting host-cell pathways to increase the potency of nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) is an important strategy for clinical investigation. Resveratrol is a natural product that inhibits cellular ribonucleotide reductase, prolonging the S phase of the cell cycle and preferentially lowering dATP levels. METHODS: We performed in vitro evaluation of resveratrol on the antiviral activity of adenosine analog tenofovir (TFV) against sensitive and drug-resistant human immunodeficiency virus type 1 (HIV-1), from subtypes B and C, in primary cells. RESULTS: Resveratrol enhanced the antiviral activity of TFV by up to 10-fold and restored susceptibility of TFV-resistant viruses. Resveratrol prevented wild-type HIV-1 from developing phenotypic resistance to TFV. Notably, resveratrol enhanced TFV activity against sensitive and resistant HIV-1 from both subtypes B and C. CONCLUSIONS: Prolonged wide-scale use of thymidine analogs in the setting of viral failure has limited the efficacy of second-line NRTI-based regimens in Africa. Moreover, the extensive use of ddI and d4T has led to high frequencies of the K65R mutation, further compromising TFV efficacy. In light of increasing resistance to commonly used NRTIs in global HIV treatment programs, targeting nucleoside biosynthesis with resveratrol, or derivatives with improved bioavailabilities, is a potential strategy to maintain, enhance, and restore susceptibility of commonly used NRTIs.
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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".