Epigenetic Inhibitors as Potential Anti-Viral Treatment against BK Polyoma Virus Associated Nephropathy
Bibliographic record
Abstract
Introduction BK polyomavirus reactivation in immuno-compromised renal transplant patients may cause rapid graft loss within six months of transplant due to serious complication i.e. BK polyoma virus associated nephropathy (BKPVAN). Due to lack of an appropriate antiviral therapy against BKV it is important to study the underlying mechanism of pathogenesis causing BKPVAN. Objective To investigate BKV pathogenesis and to determine the potential anti-viral therapy against BKPVAN. Methods Human Proximal Tubular Epithelial Cells (HPTCs) and CCD1105 cell lines were infected with BKV. In order to elucidate the epigenetic mechanism another set of cells were treated with DNA methyl transferase enzyme 1 inhibitor RG108 and Histone acetyl transferase inhibitor CPTH2. Urine samples were collected from BKV viruria/viremia positive patients. RNA/DNA was isolated to perform Methylation Specific PCR (MSP) to assess DNA methylation. Further, Real-time PCR, RNA sequencing, western blot and Immunofluorscence staining were performed. Results The downregulation of epithelial cell marker E-cadherin (CDH1) and Collagen-IV (COLIVA1) gene expression was observed in BKV infected cells, whereas, increase in expression of fibrotic marker collagen I suggests that BKV infection induces epithelial mesenchymal transition (EMT). MSP confirmed silencing of those genes through a DNA methylation mechanism by demonstrating hypermethylation of the promoters of CDH1 and COLIVA1 genes in primary cells and patient’s samples. Imunofluorescence staining has shown an increase in Vimentin and disruption of actin filaments in BKV infected cells confirming EMT. RG108 treatment, a demethylating agent, has shown altered COLIVA expression and a decrease in methylation of the promoter, demonstrating that BKV uses DNA methylation for inducing EMT and eventually fibrosis. We observed that BKV hypermethylates the RB1 gene promoter to silence it and instigate host cell division for its own replication however, RG108 treatment had demonstrated significant decrease in BKV DNA (p-value<0.037). |RNA sequencing data has revealed that GCN5 (HAT family) expression is increased in BKV infected cells which is required for viral pathogenesis and during replication whereas HATi treatment has shown significant decrease in VP1 expression (the marker of BKV infection) conferring that histone modification also plays an important role in BKV pathogenesis. Conclusion Investigating BKV pathogenesis from an epigenetic point of view revealed that BKV orchestrates EMT and pathogenesis by using a DNA methylation and histone modification mechanisms. The use of DNMTi and HATi could reverse or prevent progression of disease and block BKV replication, therefore, these epigenetic inhibitors widely used in cancer treatment, may be potentially useful as an antiviral therapy for BKPVAN. Canadian National Transplant Research Program and Alberta Transplant Institute provided fund as Fellowship to Minal Borkar-Tripathi for pursuing postdoctoral research.
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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".