The HUSH epigenetic repressor complex silences PML nuclear bodies-associated HSV-1 quiescent genomes
Bibliographic record
Abstract
Abstract Herpes simplex virus 1 (HSV-1) latently infected neurons show multiple patterns in the distribution of the viral genomes within the nucleus, at least in mouse models. One of the major patterns is characterized by the presence of quiescent HSV-1 genomes trapped in promyelocytic leukemia nuclear bodies (PML NBs) to form viral DNA-containing PML-NBs (vDCP NBs). Using a cellular model reproducing the formation of vDCP NBs we previously showed that viral genomes are chromatinized with the H3.3 histone variant modified on its lysine 9 by tri-methylation (H3.3K9me3) a chromatin mark associated with transcriptional repression. Here we identify an essential role for the HUSH complex and its SETDB1 and MORC2 effectors in the acquisition of the H3K9me3 mark on the PML NBs-associated HSV-1 and in the maintenance of HSV-1 transcriptional repression. ChiP-seq analyses highlight the association of the H3K9me3 mark with the entire viral genome. Inactivating the HUSH-SETDB1-MORC2 repressor complex prior to viral infection results in a significant reduction of H3K9me3 on the viral genome, while the overall impact on the cellular genome is minimal, except for expected changes in families of LINE1 retroelements. Depletion of HUSH, SETDB1, or MORC2, relieves the repressive state of HSV-1 in infected primary human fibroblasts as well as human induced pluripotent stem cell-derived sensory neurons (hiPSDN). We discovered that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 and MORC2 depletion capability to reactivate silenced HSV-1 in hiPSDN. Overall, our findings underscore the robust antiviral function of the HUSH-SETDB1-MORC2 repressor complex against a herpesvirus by modulating chromatin marks linked to repression, thus presenting promising avenues for novel anti-herpesvirus therapeutic strategies. Significance statement Herpes simplex virus 1 (HSV-1) is a major human pathogen, which remains latent in the trigeminal ganglia (TG) neurons of the infected individuals. Its reactivation is characterized by a variety of clinical symptoms the most severe ones being keratitis and herpesvirus encephalitis. The colonization of the CNS by the virus during the individual life is a well-known fact but the pathophysiological effects on neurons homeostasis are still underestimated. It is thus paramount to understand the molecular mechanisms that control HSV-1 latency and maintain the virus in a pseudo silent state.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".