Host restriction factor SAMHD1 limits human T-cell leukemia virus (HTLV-1) infection of primary monocytes via the innate immune sensor STING
Bibliographic record
Abstract
Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia (ATL) and other HTLV-1 associated neurological disorders. Unlike most retroviruses, cell-free HTLV-1 virions are poorly infectious and do not stably infect its primary CD4+ T lymphocyte target. However, HTLV-1 efficiently infects cells of the myeloid lineage, leading to productive infection of myeloid cells. Here, we investigate the mechanisms underlying monocyte infection by HTLV-1 and demonstrate that HTLV-1 infection induced apoptosis of monocytes in a SAMHD1-dependent manner. SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase, functions as a restriction factor that limits HIV-1 replication by reducing the availability of deoxynucleosidetriphosphates (dNTPs) required for reverse transcription. RNAi-mediated silencing of SAMHD1 inhibited monocyte apoptosis, while addition of exogenous dNTPs, or pre-treatment with azidothymidine (AZT) to block reverse transcription also inhibited apoptosis. To investigate a role for reverse transcription intermediates (RTI) in triggering apoptosis, a biotinylated 90 nucleotide RTI from the U5 region of HTLV-1 was introduced into monocytes; strikingly, the biotinylated RTI induced apoptosis and bound to the DNA sensor STING - which mediates the antiviral response via IRF3 activation. We further demonstrated that STING-mediated apoptosis in infected monocytes required the generation of a pro-apoptotic complex between IRF3 and the Bcl-2 protein Bax. These studies provide a mechanistic explanation for HTLV-1 abortive infection of monocytes and report a link between SAMHD1 restriction of reverse transcription, sensing of retroviral reverse transcription intermediates by STING, and the initiation of IRF3-Bax driven apoptosis.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".