Genetic Divergence of Human Immunodeficiency Virus Type 1 Ethiopian Clade C Reverse Transcriptase (RT) and Rapid Development of Resistance against Nonnucleoside Inhibitors of RT
Bibliographic record
Abstract
We sequenced and phylogenetically analyzed the reverse transcriptase (RT) region of five human immunodeficiency virus type 1 isolates from treatment-naive Ethiopian émigrés to Israel. Heteroduplex mobility assays were performed to confirm the clade C status of env genomic regions. The RT sequences showed that the strains clustered phylogenetically with clade C viruses, and a KVEQ-specific motif of silent mutations (amino acids 65, 106, 138, and 161, respectively) at resistance sites was present in the polymerase region of all studied Ethiopian isolates and subtype C reference strains. In addition, many other silent mutations were observed in the clade C viruses at various resistance sites. In general, the Ethiopian isolates were more closely related genotypically to a clade C reference strain from Botswana (southern Africa) than to previously sequenced Ethiopian reference strains. Genotypic analysis showed that two Ethiopian isolates naturally harbored the mutations K70R and G190A associated with resistance to ZDV and nonnucleoside reverse transcriptase inhibitors, respectively. Phenotypic assays revealed that the K70R substitution in this context did not reduce susceptibility to ZDV, whereas the G190A substitution resulted in high-level resistance to nevirapine (NVP). Moreover, variants resistant to NVP, delavirdine (DLV), and efavirenz (EFV) were more rapidly selected at lower drug doses culture with clade C than with clade B wild-type isolates. In the case of subtype C, selection with NVP and/or EFV led to the appearance of several previously unseen mutations in RT, i.e., V106M and S98I, as well as other mutations that have been previously reported (e.g., K103N, V106A, V108I, and Y181C). After selection with DLV, a polymorphism, A62A, initially observed in the Ethiopian isolate 4762, mutated to A62V; the latter is a secondary substitution associated with multidrug resistance against nucleoside RT inhibitors. Phenotypic analysis of clade C mutants selected against NVP, DLV, and EFV revealed broad cross-resistance, particularly in regard to NVP and DLV. These findings suggest that RT genotypic diversity may influence the emergence of drug resistance.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".