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.
Highlights
Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are prototypic members of the genus Simplexvirus within the herpesvirus subfamily Alphaherpesvirinae
Central to the establishment of latency is the ability of herpes simplex virus type 1 (HSV-1) to reliably switch from productive, lytic spread in epithelia to nonproductive, latent infection in sensory neurons
The present study shows that selective entry of HSV-1 into the distal axons of trigeminal neurons strongly favors the establishment of a nonproductive, latent infection, whereas nonselective infection of neurons still enables HSV-1 to induce lytic gene expression
Summary
Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are prototypic members of the genus Simplexvirus within the herpesvirus subfamily Alphaherpesvirinae. HSVs are pantropic, causing lytic infections in various tissues and cell types of a broad range of host species [1]. Humans are the only natural hosts of HSVs, and infection is almost exclusively limited to the epithelial cells and neurons of the peripheral nervous system (PNS). The portal of entry in HSV-1 infections is the oronasal mucosa, where the virus spreads rapidly with productive, lytic infection of epithelial cells [2]. Replication of HSV-1 within the PNS is tightly controlled, and further ascending spread into the central nervous system is prevented in the immunocompetent host. The ability to switch from rapidly progressing, lytic spread in epithelia to a nonproductive, latent infection in sensory neurons is fundamental to the life cycle of HSVs and other related alphaherpesviruses. The latency-associated transcript (LAT) is abundantly expressed in infected neurons, and has been shown to promote the establishment and maintenance of latency, in part because of the anti-apoptosis functions of LAT and the ability of micro-RNAs and other small non-coding RNAs encoded by LAT to interfere with productive infection [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
