Abstract
ABSTRACTHerpes simplex virus 1 (HSV-1) establishes latent infection in neurons via a variety of epigenetic mechanisms that silence its genome. The cellular CCCTC-binding factor (CTCF) functions as a mediator of transcriptional control and chromatin organization and has binding sites in the HSV-1 genome. We constructed an HSV-1 deletion mutant that lacked a pair of CTCF-binding sites (CTRL2) within the latency-associated transcript (LAT) coding sequences and found that loss of these CTCF-binding sites did not alter lytic replication or levels of establishment of latent infection, but their deletion reduced the ability of the virus to reactivate from latent infection. We also observed increased heterochromatin modifications on viral chromatin over the LAT promoter and intron. We therefore propose that CTCF binding at the CTRL2 sites acts as a chromatin insulator to keep viral chromatin in a form that is poised for reactivation, a state which we call poised latency.
Highlights
IMPORTANCE Herpes simplex virus 1 (HSV-1) is a human pathogen that persists for the lifetime of the host as a result of its ability to establish latent infection within sensory neurons
The divergent expression patterns correlate with different chromatin modifications found at the latency-associated transcript (LAT) and ICP0 promoters that are maintained despite the relative proximity of these genetic elements [21,22,23, 70, 71]
While ICP0 and other lytic gene promoters are associated with high levels of heterochromatin during latent infection, the LAT region shows enrichment of euchromatin [23, 70]
Summary
IMPORTANCE Herpes simplex virus 1 (HSV-1) is a human pathogen that persists for the lifetime of the host as a result of its ability to establish latent infection within sensory neurons. HSV-1 persists as a latent infection in sensory ganglia, during which lytic genes are epigenetically silenced, and the only viral gene products expressed abundantly are a family of noncoding RNAs known as the latency-associated transcripts (LATs) and microRNAs (miRNAs) [4,5,6,7,8]. Transcribed from the strand antisense to the LAT gene in each of the long component repeats is the ICP0 gene (Fig. 1), which encodes an immediate-early (IE) protein that serves many functions to promote lytic infection, including the transactivation of viral genes and repression of the innate immune system and intrinsic resistance [33,34,35,36,37,38,39]. In latently infected neuronal populations, ICP0 is largely repressed despite its proximity to the LAT enhancer sequences and mbio.asm.org 2
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