The genetic traits of full-length HIV sequenced from memory T cell subsets
Bibliographic record
Abstract
the availability of P-TEFb for control of latent proviral transcription.In resting memory T cells, P-TEFb is unassembled and therefore dissociated from the 7SK snRNP complex used to deliver it to genes.The extent of formation of functional P-TEFb strictly correlates with the efficiency of latency reversal and thus may be regarded as the central event required for the reversal of HIV latency.T-cell receptor stimulation of memory CD4+ T cells efficiently induces the formation of a functional 7SK snRNP complex containing P-TEFb through multiple complementary signaling pathways.Methods: These events can be traced in real time by flow cytometry and immunofluoresence microscopy using antibodies that recognize specific post-translational modifications of P-TEFb.Results: Nuclear localization of CDK9 kinase is coupled with its phosphorylation at Ser175, a marker of activated P-TEFb that we previously found to be important in allowing viral Tat to outcompete Brd4 for P-TEFb binding.Selective inhibition of Hsp90, CDK7, PI3K, mTORC1 and mTORC2 significantly suppressed the activation of P-TEFb in primary CD4+ T cells, as assessed by immunofluorescence staining for phospho-Ser175.These inhibitors also disrupted the biogenesis of P-TEFb by significantly reducing Cyclin T1 (CycT1) expression and preventing the phosphorylation of CDK9 on its T-loop at Thr186.Inhibition of Hsp90 or CDK7 kinase strongly suppressed the reactivation of latent HIV upon T-cell receptor stimulation in primary Th17 cells.Mutagenesis studies and molecular dynamics simulations based on published X-ray structures revealed that an intramolecular hydrogen bonding coordination of phospho-Thr186 by a conserved arginine triad is critical for the assembly of catalytically competent P-TEFb.Mutation of the arginine residues not only disrupted CDK9/CycT1 heterodimerization but also caused loss of phospho-Thr186 without affecting CDK9 interactions with the Hsp90/Cdc37 chaperone complex.Conclusions: Our studies focus attention on the kinases that regulate CDK9 T-loop modifications required for the biogenesis of P-TEFb and which mediate intermolecular interactions with HIV Tat for proviral gene induction.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".