Abstract
Herpes simplex virus 1 (HSV-1) latency establishment is tightly controlled by promyelocytic leukemia (PML) nuclear bodies (NBs) (or ND10), although their exact contribution is still elusive. A hallmark of HSV-1 latency is the interaction between latent viral genomes and PML NBs, leading to the formation of viral DNA-containing PML NBs (vDCP NBs), and the complete silencing of HSV-1. Using a replication-defective HSV-1-infected human primary fibroblast model reproducing the formation of vDCP NBs, combined with an immuno-FISH approach developed to detect latent/quiescent HSV-1, we show that vDCP NBs contain both histone H3.3 and its chaperone complexes, i.e., DAXX/ATRX and HIRA complex (HIRA, UBN1, CABIN1, and ASF1a). HIRA also co-localizes with vDCP NBs present in trigeminal ganglia (TG) neurons from HSV-1-infected wild type mice. ChIP and Re-ChIP show that vDCP NBs-associated latent/quiescent viral genomes are chromatinized almost exclusively with H3.3 modified on its lysine (K) 9 by trimethylation, consistent with an interaction of the H3.3 chaperones with multiple viral loci and with the transcriptional silencing of HSV-1. Only simultaneous inactivation of both H3.3 chaperone complexes has a significant impact on the deposition of H3.3 on viral genomes, suggesting a compensation mechanism. In contrast, the sole depletion of PML significantly impacts the chromatinization of the latent/quiescent viral genomes with H3.3 without any overall replacement with H3.1. vDCP NBs-associated HSV-1 genomes are not definitively silenced since the destabilization of vDCP NBs by ICP0, which is essential for HSV-1 reactivation in vivo, allows the recovery of a transcriptional lytic program and the replication of viral genomes. Consequently, the present study demonstrates a specific chromatin regulation of vDCP NBs-associated latent/quiescent HSV-1 through an H3.3-dependent HSV-1 chromatinization involving the two H3.3 chaperones DAXX/ATRX and HIRA complexes. Additionally, the study reveals that PML NBs are major actors in latent/quiescent HSV-1 H3.3 chromatinization through a PML NB/histone H3.3/H3.3 chaperone axis.
Highlights
Herpes simplex virus 1 (HSV-1) is a human pathogen with neurotropic tropism and the causal agent of cold sores and more severe CNS pathologies such as encephalitis [1]
We showed a major role of Promyelocytic leukemia (PML) nuclear bodies (NBs) in favoring the establishment of a latent state for HSV-1
A hallmark of HSV-1 latency establishment is the formation of PML NBs containing the viral genome, which we called “viral DNA-containing PML NBs”
Summary
Herpes simplex virus 1 (HSV-1) is a human pathogen with neurotropic tropism and the causal agent of cold sores and more severe CNS pathologies such as encephalitis [1]. Two transcriptional programs are associated with HSV-1 infection, the lytic cycle and latency, which differ by the number and degree of viral gene transcription. Once the nucleocapsid reaches the cell body, the virus phenotype changes from the one at the axon termini because most of the outer tegument proteins, including VP16, a viral transactivator that is essential for the onset of lytic infection, remain at the axonal tip [11,12,13]. The balance between lytic and latent transcriptional programs most likely depends on stochastic events and on undescribed neuron-associated factor(s) able to initiate the transcription of VP16 through the activation of neuro-specific sequences present in the VP16 promoter [14]. In neurons, commitment of the infectious process towards the lytic cycle or latency depends on a race between opposing infection-prone viral components and cellular features with antiviral activities
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