Neurotropic and non-neurotropic equid alphaherpesvirus 1 (EHV1) mobilize most histones within viral replication compartments
Bibliographic record
Abstract
Abstract Equid alphaherpesvirus 1 (EHV1) is a DNA virus that causes severe disease outcomes in equids. Some EHV1 strains are neurotropic and cause disease in the central nervous system, whereas others are non-neurotropic and can cause negative reproductive outcomes. The molecular mechanisms that govern pathotype of individual EHV1 strains are not understood. However, EHV1 replication in the presence of epigenetic inhibitors suggests that neurotropic and non-neurotropic EHV1 are differentially susceptible to epigenetic silencing. Aside from this evidence, little is known about EHV1 chromatin or its regulation. Here, we used fluorescence recovery after photobleaching to characterize EHV1 lytic chromatin dynamics. Infection with neurotropic or non-neurotropic EHV1 mobilized all histones. Canonical (H2A, H2B, H3.1, H4) or variant (H2A.B, H2A.Z, H2A.X, macroH2A, H3.3) core and linker H1.2 histones were equally mobilized by either strain. Thus, there were no vast differences in histone mobility during neurotropic or non-neurotropic EHV1 infection. All histones except for H2A.B were more mobile within EHV1 replication compartments (RCs) than the surrounding infected-cell chromatin. The differential mobility of histones within domains enriched for viral or cellular chromatin is consistent with distinct mechanisms to assemble and regulate the chromatin associated with viral or host DNA. Histones were further mobilized within RCs in cells in which infection had further progressed. Such mobilization indicates that increased levels of EHV1 transcription, DNA replication, or protein expression directly or indirectly mobilize histones. The high histone mobility within EHV1 RCs is consistent with assembly of EHV1 genomes in very dynamic and unstable nucleosomes. These data support a model in which EHV1 limits genome silencing by preventing stable chromatin assembly, or destabilizing the chromatin assembled, with viral genomes during lytic infection. We propose that manipulation of histone dynamics represents a novel mechanism of epigenetic regulation adopted by alphaherpesviruses to maintain genome accessibility and prevent gene silencing. Author summary DNA viruses are subjected to epigenetic regulation that silences or promotes gene expression. Multiple epigenetic mechanisms contribute to stabilize chromatin to silence gene expression or destabilize it to promote gene expression. Knowledge of the mechanisms whereby viruses prevent or overcome genome silencing and promote expression of their genes is important to understand how viruses, including alphaherpesviruses, take over the host cell to establish productive infection. Here we show that EHV1 broadly mobilizes histones within nuclear domains enriched in viral chromatin. Histone mobilization destabilizes chromatin and is consistent with the assembly of EHV1 genomes in dynamic, unstable nucleosomes. The manipulation of histone mobility is a phenomenon first described for the alphaherpesvirus herpes simplex virus 1 (HSV1). The conserved approach to dysregulate chromatin dynamics and mobilize histones represents a unique means whereby herpesviruses destabilize chromatin. Understanding the mechanisms that mobilize histones during infection will increase our general understanding of epigenetic regulation, which is important in the pathogenesis of infectious diseases and also of developmental or genetic ones. Moreover, knowledge of the processes whereby herpesviruses destabilize chromatin will support the development of novel therapeutics to maintain viral genomes in stable, silenced chromatin to prevent productive infection and development of associated diseases.
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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".