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

Date Published: September 12, 2016

Publisher: Public Library of Science

Author(s): Mohamed Ali Maroui, Aleth Callé, Camille Cohen, Nathalie Streichenberger, Pascale Texier, Julie Takissian, Antoine Rousseau, Nolwenn Poccardi, Jérémy Welsch, Armelle Corpet, Laurent Schaeffer, Marc Labetoulle, Patrick Lomonte, Chris A. Benedict.


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.

Partial Text

Herpes simplex virus 1 (HSV-1) is a neurotropic virus that establishes a life-long latent infection in the trigeminal ganglia (TG) (or Gasserian ganglia) of the infected human host. From time to time the virus asymptomatically or symptomatically reactivates from the latency stage producing epithelial lesions, most of the time on the face but also in the eye, inducing severe pathologies such as keratitis [1]. HSV-1 infection is also associated with pathologies of the central nervous system (CNS), such as encephalitis, especially after primary infection of newborn children with deficiencies in their innate immunity due to genetic alteration of two genes coding proteins involved in the intrinsic antiviral response [2]. In mouse models reproducing latent infection, HSV-1 has also been shown to lead to brain pathologies following reactivation through retrograde transport of the viral particles towards the CNS [3,4].

The interaction of chromosomal loci with their nuclear environment affects the transcriptional activity of particular genes [77]. Nuclear architecture is thus likely to greatly influence the fate of infection with nuclear-replicating viruses, such as herpesviruses. In this study, we demonstrated that the interaction of latent HSV-1 genomes with the nuclear environment is impacted by the activity of cellular components, such as PML-NBs and type I IFNs, but also by viral features such as the ability of the virus to enter the lytic cycle and to express ICP0. During establishment of HSV-1 latency in the mouse model, viral genomes adopt several nuclear patterns before reaching the two main patterns that are found during stable latency. The nuclear distribution of viral genomes changes greatly until 14 dpi, and stabilizes thereafter. This is in agreement with previous reports of extinction of lytic gene expression, acquisition of chromatin markers, and expression of LAT, which are major molecular features of HSV-1 latency and usually evident by 14 dpi [78–80]. This indicates that the battle between the virus and the infected neurons involves multiple changes in the interaction between the viral genomes and the nuclear environment until reaching a stable situation suitable for both the virus and the host cell.




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