Defining a Molecular Mechanism of Synergy between Nucleoside and Nonnucleoside AIDS Drugs
Bibliographic record
Abstract
Combination therapies treating human immunodeficiency virus type 1 (HIV-1) infection delay the emergence of drug-resistant virus and exhibit synergistic inhibition. This synergy is observed within the two classes of inhibitors that target the essential viral reverse transcriptase (RT): the chain-terminating nucleoside analogs (NRTIs) and the allosteric nonnucleosides (NNRTIs) that bind in a pocket distinct from the active site. A general mechanism to define the molecular basis for synergy between these two classes remains to be elucidated. Previous mechanistic studies from our laboratory (Spence, R. A., Kati, W. M., Anderson, K. S., and Johnson, K. A. (1995) Science 267, 988-993) have shown that the natural deoxynucleoside triphosphate and the NNRTI can simultaneously bind to their respective sites. This work also suggests communication between the two sites, since the inhibition of RT by NNRTIs is manifested through a remote effect on the chemical step. This interplay between the two sites offers a plausible hypothesis for understanding synergy in which binding of NNRTIs modulates the chain termination by NRTIs. The present study supports this hypothesis by illustrating that the clinically approved NNRTIs, nevirapine and efavirenz, inhibit the ATP-mediated removal of AZTMP, d4TMP, ddCMP, (-)3TCMP, (-)FTCMP, and (+)3TCMP, thereby prolonging the effectiveness of chain termination. This inhibition is mediated through an effect on both the rate of the chemical step and binding of ATP, resulting in an overall decrease in efficiency of removal. This work substantiates communication between the two binding pockets, the sustained use of combination therapy to treat HIV infection, and a molecular basis for understanding synergy.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 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".