title: Entry of herpes simplex virus type 1 (HSV-1) into the distal axons of trigeminal neurons favors the onset of nonproductive, silent infection.
abstract: Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons.
authors.affiliation: University Hospital Münster, Institute of Medical Microbiology-Clinical Virology, Münster, Germany.
authors.forename: Wali
authors.initials: W
authors.lastname: Hafezi
authors.forename: Eva U
authors.initials: EU
authors.lastname: Lorentzen
authors.forename: Bodo R
authors.initials: BR
authors.lastname: Eing
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: King
authors.forename: Barbara
authors.initials: B
authors.lastname: Klupp
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Mettenleiter
authors.forename: Joachim E
authors.initials: JE
authors.lastname: Kühn
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D058345:Asymptomatic Infections; D001369:Axons / Q000821:virology*; D002478:Cells, Cultured; D002642:Chick Embryo; D015967:Gene Expression Regulation, Viral; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D011558:Herpesvirus 1, Suid / Q000472:pathogenicity; D018258:Herpesvirus 2, Human / Q000472:pathogenicity; D017874:Immediate-Early Proteins / Q000235:genetics; D015533:Transcriptional Activation; D012668:Trigeminal Ganglion / Q000821:virology*; D053586:Virus Internalization; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000081:Acetamides; D017405:Herpes Simplex Virus Protein Vmw65; D017874:Immediate-Early Proteins; C014026:hexamethylene bisacetamide