HIV Nef disrupts Lck signaling by inducing aberrant phosphorylation of its substrates
Bibliographic record
Abstract
Human in vitro studies of HIV Nef on TcR proximal signaling have been controversial and have not provided an integrated picture of its impact. Tyrosine (Y) phosphorylation (pY) of Lck and its substrates (CD3ζ, Zap-70) was investigated in vivo, in Nef-expressing transgenic (Tg) thymocytes. In Tg cells, Lck was mis-localized and activated, but the pY-CD3ζ levels were unexpectedly lower, both constitutively and after anti-CD3ε Ab stimulation. Nef also favors the hyperphosphorylation of the Lck Y505 site and the accumulation of doubly phosphorylated (Y394, Y505) Lck. In contrast, after anti-CD3ε+anti-CD4 Ab stimulation, Nef decreased Lck activity and Lck was deprived of its pY partners. In Nef and LckY505F Tg thymocytes, Lck had similar activity but distinct LckY505 levels, Zap-70 pY phosphorylation, and Zap-70 activity, suggesting a different mode of Lck activation. Western blot analysis of Zap-70 with pY site-specific mAb showed modest enhanced levels of Zap-70pY292 and Zap-70pY493 (the latter required for its full activation) constitutively and after anti-CD3ε Ab stimulation, consistent with elevated Tg LATpY and suggesting a semiactive kinase. In fact, phenotypes of Nef Tg mice are very similar to those of mice harboring semiactive Zap-70 mutants. After anti-CD3ε+anti-CD4 stimulation, Tg Zap-70 activity and Zap-70pY493 levels were severely decreased, but Zap-70pY292 and Zap-70pY319 levels were barely affected, suggesting qualitative Lck defect. Rescue of Nef-mediated CD4+ T-cell loss with LckY505F in double (Nef × LckY505F) Tg mice correlated with greatly enhanced levels of Zap-70pY and Zap-70 activity. Thus, Nef impacts Lck in a unique way, triggering it to mis-phosphorylate its substrates.
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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".