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.

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

“…HSV-1 tegument contains virion protein 16 (VP16, also known as UL48 and a-TIF) (Zhu & Courtney, 1994) and immediate-early proteins ICP0 (Yao & Courtney, 1992) and ICP4 (Bibor-Hardy & Sakr, 1989). Following virus entry into most, if not all cell types, but especially neurons cultured from human or rat dorsal root ganglia, HSV-1 VP16/UL48, an integral part of the virus tegument (Elliott et al, 1995), is shed from the nucleocapsid as it undergoes transaxonal retrograde transit (Antinone & Smith, 2010;Hafezi et al, 2012). Free VP16/UL48 in the axon and cytosol (Aggarwal et al, 2012) associates with host cell factor (HCF)-1 through a conserved tetrapeptide motif found in most basic leucine-zipper proteins (Freiman & Herr, 1997).…”

Mutation of UL24 impedes the dissemination of acute herpes simplex virus 1 infection from the cornea to neurons of trigeminal ganglia

“…This effect is possibly due to loss of specific transcription factors from the tegument of the incoming virion as it makes its way along the axon to the nucleus, thus shifting the balance between viral lytic gene expression and latency (Hafezi et al, 2012;Roizman & Sears, 1987). In our experiments, we did not restrict infection of neurons to a specific substructure of the cell.…”

“…It has recently been shown that infection of neurons at the level of the cell stroma favours an acute infection; in contrast, infecting neurons through their axonal termini favours a latent infection (Hafezi et al, 2012). This effect is possibly due to loss of specific transcription factors from the tegument of the incoming virion as it makes its way along the axon to the nucleus, thus shifting the balance between viral lytic gene expression and latency (Hafezi et al, 2012;Roizman & Sears, 1987).…”

Latence et réactivation du virus de l’herpès simplex de type 1 (HSV-1)

“…Dès sa pénétration dans le noyau des cellules épithéliales, le génome viral interagit avec des histones, mais sans aboutir à une chromatini- Glycoprotéines transcripts), seul gène viral à s'exprimer pendant la latence [1,2]. Dans les neurones sensitifs, VP16 n'est pas efficacement transportée le long des axones et n'arrive pas aux noyaux [16,17]. De plus, dans les neurones, HCF1 est détectée seulement dans le cytoplasme et elle est incapable d'interagir avec VP16, car inaccessible [18].…”

“…Il en résulte que le complexe VP16/ OCT1/HCF1 ne se forme pas, ce qui se traduit par un déficit de l'expression des gènes très précoces (Figure 2). Une étude récente apporte une contribution majeure concernant le rôle de VP16 dans les étapes très précoces de l'infection latente [17] : des explants de ganglions trijumeaux ont été mis en culture dans un dispositif à deux compartiments, permettant de séparer les corps cellulaires (compartiment central) des terminaisons nerveuses (compartiment périphérique). En introduisant le virus dans l'un ou l'autre de ces compartiments, on constate que l'infection des corps cellulaires conduit à une infection lytique, alors que l'infection des terminaisons nerveuses mène presque toujours à une infection quiescente, caractérisée par une très faible expression des gènes lytiques et une forte transcription des gènes LAT.…”