Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment

Abstract

Herpes simplex virus 1 (HSV-1) establishes latency in trigeminal ganglia (TG) sensory neurons of infected individuals. The commitment of infected neurons toward the viral lytic or latent transcriptional program is likely to depend on both viral and cellular factors, and to differ among individual neurons. In this study, we used a mouse model of HSV-1 infection to investigate the relationship between viral genomes and the nuclear environment in terms of the establishment of latency. During acute infection, viral genomes show two major patterns: replication compartments or multiple spots distributed in the nucleoplasm (namely “multiple-acute”). Viral genomes in the “multiple-acute” pattern are systematically associated with the promyelocytic leukemia (PML) protein in structures designated viral DNA-containing PML nuclear bodies (vDCP-NBs). To investigate the viral and cellular features that favor the acquisition of the latency-associated viral genome patterns, we infected mouse primary TG neurons from wild type (wt) mice or knock-out mice for type 1 interferon (IFN) receptor with wt or a mutant HSV-1, which is unable to replicate due to the synthesis of a non-functional ICP4, the major virus transactivator. We found that the inability of the virus to initiate the lytic program combined to its inability to synthesize a functional ICP0, are the two viral features leading to the formation of vDCP-NBs. The formation of the “multiple-latency” pattern is favored by the type 1 IFN signaling pathway in the context of neurons infected by a virus able to replicate through the expression of a functional ICP4 but unable to express functional VP16 and ICP0. Analyses of TGs harvested from HSV-1 latently infected humans showed that viral genomes and PML occupy similar nuclear areas in infected neurons, eventually forming vDCP-NB-like structures. Overall our study designates PML protein and PML-NBs to be major cellular components involved in the control of HSV-1 latency, probably during the entire life of an individual.

The SP100 component of ND10 enhances accumulation of PML and suppresses replication and the assembly of HSV replication compartments

“…In addition, we noted delays in the degradation of SP100 mediated by ICP0, consistent with reduced colocalization of ICP0 with structures containing SP100 and Daxx (31). Because ND10 bodies appear to be predecessors of viral replication compartments in which viral DNA is made and packaged, the results suggest that ICP0 homes in on ND10 bodies to degrade PML and at the same time initiate the formation of replication compartments (33)(34)(35)(36)(37). In this report, we focus on SP100.…”

Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency

“…Multiple factors impact HSV latency and reactivation including the status of the chromatin structure of the latent viral genome (Bloom et al, 2010; Knipe and Cliffe, 2008; Lieberman, 2016), neuronal antiviral responses (Enquist and Leib, 2016; Maroui et al, 2016; Rosato and Leib, 2015), and microRNAs that suppress lytic gene expression (Flores et al, 2013; Pan et al, 2014). Once considered to be a suppressed static state, the concept of HSV latency has evolved to a more dynamic model (Bloom, 2016) to account for HSV-specific immune surveillance in latently infected ganglia (St Leger and Hendricks, 2011), viral subclinical shedding (Wald and Corey, 2007), and the detection of lytic gene expression in individual latent neurons (Russell and Tscharke, 2016).…”

Promyelocytic Leukemia (PML) Nuclear Bodies (NBs) Induce Latent/Quiescent HSV-1 Genomes Chromatinization Through a PML-NB/Histone H3.3/H3.3 Chaperone Axis

“…Promyelocytic leukemia (PML) nuclear bodies (NBs) (also called ND10) are proteinaceous entities aimed to control viral infection as part of the cell and nucleus-associated intrinsic antiviral response but also through innate immunity associated with the interferon (IFN) response. Our recent studies have shown that PML-NBs tightly associate with incoming HSV-1 genomes in the nucleus of infected TG neurons in mouse models and in primary TG neuron cultures [15,16]. Hence, PML-NBs reorganize in structures called viral DNA-containing PML-NBs (vDCP-NBs), which are formed at early times during the process of HSV-1 latency establishment and persist during latency per se in a large subset of latently infected neurons in a mouse model of infection [15].…”

“…Therefore, although at the entire TG level HSV-1 latency could be a dynamic process from a transcriptional perspective, at the single neuron level, a strict, transcriptionally silent, quiescence can be observed, and vDCP-NB-containing neurons are major contributors of this latent/quiescent HSV-1 state. In humans, vDCP-NB-like structures have also been observed in latently infected TG neurons [16], suggesting that vDCP-NBs are probably molecular hallmarks of the HSV-1 latency process, including in the natural host.…”

“…The histone variant H3.3 itself localizes in PML-NBs in proliferating and senescent cells, linking PML-NBs with the chromatin assembly pathway independently of replication [35–37]. Because vDCP-NBs contain DAXX and ATRX [15,16,38], their involvement in the chromatinization of incoming HSV-1 genomes and/or long-term maintenance of chromatinized HSV-1 genomes is thus plausible.…”