The role of innate polymorphisms in drug selected protease and reverse transcriptase mutations in HIV
Bibliographic record
Abstract
This doctoral thesis includes four projects.The first project explored the role of innate HIV genetic polymorphisms in drug-selected mutations.By means of drug selection experiments, we comparatively evaluated emergent mutations in protease and reverse transcriptase in HIV-1 and HIV-2 subtypes.Genotypic and phenotypic analyses were used to determine time to appearance of resistance mutations and the levels of drug resistance, respectively.Natural polymorphisms in HIV-2 seemed to facilitate selection of protease inhibitor (PI) resistance: The acquisition of the I54M, I84V, L90M and L99F mutations resulted in multi-PI-resistant viruses.Nucleoside reverse transcriptase inhibitor (NRTI) combinations preferentially selected for the K65R mutation in HIV-1 subtype C, while in HIV-1 subtype B, and HIV-2 cultures favored the development of M184I.The K65R mutation was not detected in HIV-2 selections.These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and the role that innate polymorphisms may have in dictating antiretroviral resistance pathways.In the second project, we studied the relationship between mutations in the RNase H domain on viral susceptibility to nucleoside analogues.Our results showed that although some mutations were observed in the connection domain, the presence of the L74V and M184V mutations was the most significant determinant of phenotypic resistance to ZDV in patients with thymidine analog-associated mutations.The third project performed a near full-length genomic analysis of a novel HIV-1 recombinant involving subtypes A1 and C in Quebec.The fourth project evaluated the genetic diversity of an HIV-1 isolate that was referred to us as a suspected case of superinfection.We evaluated this isolate"s sequences from different time points and determined that the sequence was a unique A1/C intersubtype recombinant at baseline and not a case of superinfection.We concluded that DEDICATION This Ph.D. thesis is dedicated to my dear wife Alechia Alemka and the kids Dylan and Ryan.Thank you all for being there throughout this work and for providing me
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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".