Continuous antiretroviral therapy induces progressive senescence-like reprogramming of alveolar macrophages
Bibliographic record
Abstract
Abstract Background Advances in antiretroviral therapy (ART) have substantially improved the lives of people with HIV (PWH) and reduced HIV acquisition through pre-exposure prophylaxis (PrEP). However, the long-term effect of ART on the physiological state of cells remains poorly understood. Despite the success of ART in preventing the progression of HIV infection to AIDS, aging PWH are suffering from a disproportional burden of non-AIDS comorbidities, including lung diseases. Methods Given the central function of alveolar macrophages (AM) in pulmonary immunity, we evaluated the impact of nucleoside reverse transcriptase inhibitors (NRTI) based ART on AM of PWH and people on PrEP. We employed a retrospective cross-sectional design and evaluated the effects of continuous exposure to ART in the epigenetic and transcript of AM at bulk and single-nucleus multiomics levels. Results We showed that continuous NRTI-based ART induces a progressive senescence-like pro-inflammatory state in AM, characterized by increased constitutive epigenetic and transcriptomic priming of genes involved in cell cycle arrest (e.g., CDKN1A /p21), components of the senescence-associated secretory phenotype (e.g., IL1A , IL6R, and CXCL8 ), as well as transcription factors subunits of the AP-1 family (e.g., FOSL1, JUN ). At the AM single nucleus level we discovered a coordinated gene regulatory network linking key pro-inflammatory transcription factors to the transcriptomic alterations induced by ART. The senescence ART-linked epigenetic and transcriptomic changes were strongly dependent on the duration of ART and irrespective of HIV infection. A secondary time independent ART effect was observed for interferon signaling genes. This effect was more pronounced in people on PrEP and impaired the AM response to ex vivo challenge with SARS-CoV-2. Conclusion Combined, our data indicated that continuous NRTI-based ART promoted a dysregulated physiological state in AM, potentially contributing to age-related pulmonary comorbidities in PWH, such as COPD, pulmonary fibrosis, and asthma. The results of our study advocate for optimized or adjuvant therapies to mitigate potential long-term adverse effects of ART for people on PrEP and PWH.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".