Unmasking two stages of interferon signaling in dendritic cells infected with HIV-1
Bibliographic record
Abstract
Abstract Myeloid dendritic cells (DCs) have the innate capacity to sense pathogens and mount counteroffensive responses, which include the production of type I and type III interferons (IFN). In the case of HIV-1 infection, DCs can internalize and present viral antigens, but the majority of DCs are not productively infected due to restriction at the level of reverse transcription. Consequently, DCs do not efficiently ‘sense’ HIV-1, fail to produce IFN, do not mature, and cannot program appropriate adaptive immune responses. To improve our understanding of how IFN and cell maturation are regulated in monocyte-derived DCs, we have used systems analyses to study how DCs respond to HIV-1 after removing the block to reverse transcription with the lentiviral protein Vpx. We have profiled changes in open chromatin during infection using an assay for transposase-accessible chromatin (ATAC-seq), and have tracked the kinetics of gene expression in parallel. Using antiretroviral drugs and virus mutants to separate stages of the life cycle, we have determined that at least two signals cooperate to drive innate immune responses during HIV-1 infection: the first coming from the cytoplasmic sensor, cGAS, which is known to recognize reverse transcribed HIV cDNA, and the second from an unrelated pathway engaged after virus integration. Moreover, by interrogating infection in combination with a battery of classic innate agonists we have found that HIV-1 primes DCs to produce IFN, even in the presence of certain antiretroviral drugs. Our studies demonstrate that robust IFN production in response to HIV-1 infection depends on the coordinated action of distinct transcription factors and illuminate key pathways that regulate innate immunity in myeloid cells.
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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 | 0.000 |
| 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".