Impairment of viral replication capacity by nef alleles from HIV elite controllers
Bibliographic record
Abstract
Background Elite controllers (EC) are HIV-1 infected persons who can spontaneously control viremia to extremely low levels. Because it is known that nef is required for HIV1 replication and pathogenesis in vivo, we wish to clarify how HIV-1 nef plays a role in acquiring EC phenotype. Materials and methods Viral RNAs were extracted from plasma samples of 45 ECs and 48 chronic progressors (CP) and used for amplification of nef by RT-PCR. The amplified products were cloned into a plasmid and subsequently sequenced. A representative nef clone was selected for each patient and cloned into an NL43 proviral plasmid backbone. Infectious recombinant viruses were prepared by transfecting 293T cells with these resultant proviral clones and tested for their viral replication capacity in PBMCs obtained from multiple healthy donors. Viral replication was monitored by measuring the concentration of p24 Gag in the culture supernatant by p24 ELISA every 3 days. The same virus stocks were further tested for their infectivity using TZM-bl cells. Results All nef alleles isolated from EC and CP had intact ORFs. Phylogenetic analysis revealed no specific lineage or clustering, suggesting the absence of common genetic defects in EC-derived nef alleles. All viruses expressing patient-derived nef showed a wide range of viral replication in PBMC, confirming the importance of nef alleles in the enhancement of viral replication capacity. The viruses harboring EC-derived nef replicated and peaked on Day 12 after infection or even later; whereas the viruses harboring CP-derived nef peaked on Day 9. Also, the peak level of p24 values was significantly lower in the EC-nef viruses than in the CP-nef viruses. Because Nef activity is highly dependent on PBMC donors, we tested 4 different donors’ PBMC and compared the initial burst of their viral replication at Day 9. In all donors’PBMC, viruses carrying EC-nef displayed lower p24 values than those carrying CP-nef, suggesting that the viral replication capacity was much impaired by nef alleles in EC. Corroboratively, in viral infectivity assay in TZM-bl cells, the EC-nef viruses showed significantly lower infectivity than the CP-nef viruses. Conclusion
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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 | 0.001 |
| 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".