The Fate of Incoming HSV-1 Genomes Entering the Nucleus

Abstract

Herpesvirus genomes enter the eukaryotic nucleus as large linear double stranded DNA molecules that are free of any proteins (naked DNA). Once inside the nucleus, the HSV-1 genomes immediately associate with proteins that will be instrumental in the organization and regulation of these genomes.These initial interactions are thought to determine the fate of the infecting genomes. In general, the host cell has evolved several mechanisms to suppress viral genomes and induce latent or abortive infections. On the other hand, the virus has evolved to use viral and cellular factors to promote lytic infection. Recent findings suggest that not all viral genomes in the infected nucleus will develop progeny and that not all genetically identical cells will support successful virus propagation. Thus, the decision between different fates of infection is determined at both single-cell and single-genome levels.Here we summarize current knowledge on the conditions and interactions that lead to each outcome and discuss the unknown determinants.

pUL36 de-ubiquitinase activity augments both the initiation and progression of lytic virus infection in IFN–primed cells

“…Several studies suggested that HSV-1 genomes injected into the nucleus of IFN pre-treated cells cannot initiate transcription (65,66). This restriction is exacerbated in HSV-1 mutants lacking the viral E3 RING ubiquitin ligase ICP0 (54,(67)(68)(69). We previously reported that treatment with IFN-β reversibly silenced MCMV infection in endothelial and fibroblast cells (56).…”

Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

“…During latency, viral transcription is severely restricted, there is no significant expression of any viral proteins, or viral DNA replication, and no infectious virions are produced. The mechanisms that result in the silencing of the viral genomes are likely multifactorial and remain incompletely characterized, but there is a general consensus in that chromatin epigenetics play a major role ( Bloom et al, 2010 ; Cliffe and Wilson, 2017 ; Knipe and Cliffe, 2008 ; Lieberman, 2016 ; Nicoll et al, 2012 ; Singh and Tscharke, 2020 ; Washington et al, 2019 ); recently reviewed in ( Kobiler and Afriat, 2021 ).…”

“…Briefly summarizing, histone PTM associated with transcription ( e.g., H3 K9ac, K14ac, K4me3) have been consistently reported to associate with transcribed HSV-1 genes during lytic infections and histone PTM normally associated with silencing ( e.g., H3K9me2/3 or K27me3), with genes transcribed to only low levels or not at all ( Fig. 7 ) (recently reviewed in Kobiler and Afriat, 2021 ). VP16 recruits to the IE promoters the HDM LSD1/KDM1A to remove H3K9me3, which is associated with silencing.…”

“…Phosphonoacetic acid (PAA-which inhibits DNA replication and thus the transcription of only the strictly L genes) did not result in less accessibility to the L genes, and the (largely transcribed) viral genomes had similar accessibility than in the untreated infections ( Hu et al, 2019 ). As a caveat, population analyses cannot resolve any small subpopulation of transcribed genomes from a vast majority of non-transcribed ones and some populations of genomes in the same infected cell are transcribed whereas other are not ( Cohen and Kobiler, 2016 ; Kobiler and Afriat, 2021 ; Kobiler et al, 2010 , 2011 ). Nonetheless, the simultaneous changes in accessibility and general transcription activity are the most consistent with any model proposing that chromatin accessibility regulates the transcriptional competency of the HSV-1 genomes, whereas the transcription level of any given gene is regulated by promoter-specific factors, likely in only a minority of the genomes in the cell ( Hu et al, 2019 ).…”

“…Whereas in cellular chromatin competency is often marked by specific epigenetic PTM at regions spanning the promoters of the regulated genes, which are sometimes marked with ambivalent or poised PTM ( Barski et al, 2007 ; Blanco et al, 2020 ; Sen et al, 2016 ), the competency of the viral chromatin appears to be determined by the overall dynamics of the viral chromatin on the entire genomes ( Fig. 8 ) ( Hu et al, 2019 ); recently reviewed in ( Kobiler and Afriat, 2021 ). These dynamics themselves appear to be in part determined by global enrichment in particular PTM in the viral chromatin, in that the PTM change along infection as HSV-1 DNA accessibility does ( Gao et al, 2020 ; Hu et al, 2019 ).…”