Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment.
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.
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), team Chromatin Assembly, Nuclear Domains, Virus, Lyon, France.
Mohamed Ali
MA
Maroui
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), team Chromatin Assembly, Nuclear Domains, Virus, Lyon, France.
Aleth
A
Callé
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), team Chromatin Assembly, Nuclear Domains, Virus, Lyon, France.
Camille
C
Cohen
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène (INMG), team Nerve-Muscle Interactions, Lyon, France.|Univ Lyon, Centre Hospitalier Universitaire de Lyon, Hospices Civils de Lyon, Centre de Pathologie et Neuropathologie Est, Bron, France.
Nathalie
N
Streichenberger
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), team Chromatin Assembly, Nuclear Domains, Virus, Lyon, France.
Pascale
P
Texier
Institut de Biologie Intégrative de la Cellule (I2BC), Département de Virologie, Gif-sur-Yvette, France.
Julie
J
Takissian
Institut de Biologie Intégrative de la Cellule (I2BC), Département de Virologie, Gif-sur-Yvette, France.|Université Paris Sud, Centre Hospitalier Universitaire de Bicêtre, Service d'Ophthalmologie, Le Kremlin-Bicêtre, France.
Antoine
A
Rousseau
Institut de Biologie Intégrative de la Cellule (I2BC), Département de Virologie, Gif-sur-Yvette, France.
Nolwenn
N
Poccardi
Ecole Normale Supérieure de Lyon, CNRS UMR 5308, INSERM U 1111, Centre International de Recherche en Infectiologie (CIRI), team Immunobiologie des infections virales, Lyon, France.
Jérémy
J
Welsch
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), team Chromatin Assembly, Nuclear Domains, Virus, Lyon, France.
Armelle
A
Corpet
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, Institut NeuroMyoGène (INMG), team Nerve-Muscle Interactions, Lyon, France.
Laurent
L
Schaeffer
Institut de Biologie Intégrative de la Cellule (I2BC), Département de Virologie, Gif-sur-Yvette, France.|Université Paris Sud, Centre Hospitalier Universitaire de Bicêtre, Service d'Ophthalmologie, Le Kremlin-Bicêtre, France.
Marc
M
Labetoulle
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U 1217, LabEx DEVweCAN, Institut NeuroMyoGène (INMG), team Chromatin Assembly, Nuclear Domains, Virus, Lyon, France.
Patrick
P
Lomonte
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D016679:Genome, Viral / Q000235:genetics*; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000821:virology; D017735:Virus Latency / Q000235:genetics*
D002352:Carrier Proteins; D007370:Interferon Type I; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D015534:Trans-Activators; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta