Neuronal pathways for the propagation of herpes simplex virus type 1 from one retina to the other in a murine model

Labétoulle, Marc; Kucera, Paul; Ugolini, Gabriella; Lafay, Florence; Frau, E; Offret, H; Flamand, Anne

doi:10.1099/0022-1317-81-5-1201

Cited by 34 publications

(22 citation statements)

References 42 publications

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“…HSV-1 antigens were detected on SC16-and SC16 110LacZ-infected cryosections by a peroxidase antiperoxidase assay, using a polyclonal anti-HSV-1 antibody (38).…”

Section: Methodsmentioning

confidence: 99%

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Herpes Simplex Virus Type 1 Latently Infected Neurons Differentially Express Latency-Associated and ICP0 Transcripts

Maillet

Naas

Crépin

et al. 2006

J Virol

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Herpes simplex virus type 1 (HSV-1) is a human neurotropic virus, which establishes lifelong latent infection. During the acute phase of infection, viral replication is characterized by the expression of immediate early (IE), early, and late genes in an ordered cascade that leads to the release of infectious particles that can attach to nerve endings. Following axonal transport to neuronal cell bodies, HSV-1 can either replicate or persist in a latent state in the infected host (62).During latency infectious virus cannot be detected in neuronal tissues (62). The viral genome is circularized, complexed with histones, and maintained in a repressed state with the exception of the latency-associated transcripts (LATs) that are encoded within the repeats flanking the unique long region of the HSV-1 genome (12, 33, 60). The LATs (2 kb and 1.5 kb in size) are stable unpolyadenylated introns that are retained within the nuclei of latently infected neurons (reviewed in references 33 and 56) and are spliced from a primary 8.3-kb transcript (19). Their unusual stability has been related to modifications in the consensus sequences of splicing (84), resulting in an unstable 6.3-kb spliced exon (13, 85) and a stable 2-kb LAT intron that is expressed during both acute and latent infections (73,84). During latent neuronal infection, the 2-kb LAT may undergo subsequent splicing that results in a 1.5-kb LAT (1,46,70). The functions of LATs are not yet clearly understood, but mutational analyses and transfection assays of LATs strongly suggest that they have a key role in establishment of latency and/or viral reactivation (29,31,53,64,71,77), besides their antiapoptotic, anti-interferon, and proneuronal survival properties (24,32,52,54,55,78).Several studies failed to detect lytic viral gene expression during HSV-1 latency (20,33). However, some studies reported the detection of transcripts from genes encoding the immediate-early viral protein ICP4 and the early viral protein thymidine kinase (TK) in latently infected trigeminal ganglion (TG) neurons (9, 34). This observation was initially interpreted as a possible result of spontaneous reactivation (33). Since the gene encoding the ICP0 protein of HSV-1 is contained entirely within the region of the HSV-1 genome encoding LATs (reviewed in reference 3), it might be transcribed during latency, as recently reported by Chen et al. for latently infected TG neurons (10). ICP0 is the first viral protein produced during the productive cycle and is thus classically considered a relevant indicator of early-stage reactivation (18,59,65). It nonspecifically transactivates both viral and cellular promoters (18,25,42) and plays a crucial role in the initiation of productive infection following low-multiplicity infections of cells in culture (7,8,17,63). ICP0 is able to initiate both viral gene expression from quiescent genomes in cells in culture and viral reactivation from latently infected sensory neurons in vivo (6, 26, 27,

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“…HSV-1 antigens were detected on SC16-and SC16 110LacZ-infected cryosections by a peroxidase antiperoxidase assay, using a polyclonal anti-HSV-1 antibody (38).…”

Section: Methodsmentioning

confidence: 99%

“…Wild-type HSV-1 strain SC16 (30) and the recombinant strain SC16 110LacZ (41), which contains an ICP0 promoter-driven lacZ inserted into the nonessential US5 gene of HSV-1, were used. Viruses were propagated and titrated as previously described (37)(38)(39).…”

Section: Methodsmentioning

confidence: 99%

Herpes Simplex Virus Type 1 Latently Infected Neurons Differentially Express Latency-Associated and ICP0 Transcripts

Maillet

Naas

Crépin

et al. 2006

J Virol

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“…Because sympathetic neurons have their origin in the thoracolumbar cord and parasympathetic neurons arise in the sacral cord, we hypothesized that these findings may be related to viral infection of autonomic ganglia (2). Both HSV-1 and HSV-2 are able to infect autonomic neurons (3,5,7,10,12,(14)(15)(16)(17). HSV-2 infection of autonomic neurons can give rise to transient bladder paralysis in humans, and latently infected murine parasympathetic neurons express the latency-associated transcript (12).…”

mentioning

confidence: 99%

Spread of Herpes Simplex Virus to the Spinal Cord Is Independent of Spread to Dorsal Root Ganglia

Ohashi

Bertke

Patel

et al. 2011

J Virol

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Levels of herpes simplex virus 1 (HSV-1) and HSV-2 DNA in dorsal root ganglia (DRG) and spinal cord (SC) were quantified after inoculation of guinea pig genitals and footpads. In genital infection, viral DNA reached SC and DRG simultaneously (at 2 to 3 days after inoculation) but was more abundant in SC than in DRG. After inoculation of footpads, which lack parasympathetic innervation, the viruses spread more efficiently to DRG than to SC. These results show important differences between genital and footpad infections, including independence of spread to DRG and SC, and imply that autonomic neurons may play an important role in the pathogenesis of viral latency after genital inoculation.The related species herpes simplex virus 1 (HSV-1) and HSV-2 exhibit differences in latency and recurrence patterns. While both viruses establish latency in sensory ganglia and reactivate to cause recurrent disease, HSV-1 reactivates more efficiently from trigeminal ganglia to cause cold sores or keratitis and HSV-2 reactivates more efficiently from lumbosacral dorsal root ganglia (DRG) to cause genital herpes (8). HSV-1 and HSV-2 also display different tropisms for nociceptive sensory neurons, with HSV-1 more likely to be detected during latency in murine neurons displaying the surface marker A5 and HSV-2 in those displaying KH10 (9). Both of these findings are associated with HSV-1 or HSV-2 viral species-specific latency-associated transcript (LAT) sequences (9, 18).Although most studies have focused on viral latency in sensory neurons of either the dorsal root or trigeminal ganglia, we recently showed that levels of virus DNA in spinal cord exceeded those in the corresponding DRG, suggesting that other sites of latency may be important (1). After genital infection of guinea pigs, the quantities of latent HSV-1 DNA are greater in the thoracolumbar spinal cord than in the sacral spinal cord, while latent HSV-2 DNA is more abundant in the sacral spinal cord. Mutations in the LAT did not influence this tropism for different spinal cord levels. Because sympathetic neurons have their origin in the thoracolumbar cord and parasympathetic neurons arise in the sacral cord, we hypothesized that these findings may be related to viral infection of autonomic ganglia (2). Both HSV-1 and HSV-2 are able to infect autonomic neurons (3,5,7,10,12,(14)(15)(16)(17). HSV-2 infection of autonomic neurons can give rise to transient bladder paralysis in humans, and latently infected murine parasympathetic neurons express the latency-associated transcript (12). Viral infection of autonomic ganglia is difficult to study directly in animal models of HSV-2 infection because perigenital ganglia are very small, are located in the perigenital fat, and are difficult to identify. In the present study, we used genital (6) and footpad models of HSV infection to further examine these phenomena that are potentially related to differences in autonomic neuronal infections with HSV-1 and HSV-2.To further investigate the spread of virus to the spinal cord, we examined ...

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“…In a murine model, retinitis of the contralateral eye was observed within three days after intravitreal inoculation with a highly neurovirulent HSV-1 strain (Labetoulle et al, 2000). The time course of virus spread and immunohistological findings support the theory of non-synaptic virus transfer between neurones and glia cells in the chiasma opticum leading to the infection of the contralateral eye (Labetoulle et al, 2000). This is clinically relevant, since specific antiviral therapy reduces the risk for bilateral ARN (Palay et al, 1991).…”

Section: Viral Pathogenesismentioning

confidence: 52%

Virus Diagnostics and Antiviral Therapy in Acute Retinal Necrosis (ARN)

Rautenberg¹,

Hillenkamp²,

Grancicova³

et al. 2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Neuronal pathways for the propagation of herpes simplex virus type 1 from one retina to the other in a murine model

Cited by 34 publications

References 42 publications

Herpes Simplex Virus Type 1 Latently Infected Neurons Differentially Express Latency-Associated and ICP0 Transcripts

Herpes Simplex Virus Type 1 Latently Infected Neurons Differentially Express Latency-Associated and ICP0 Transcripts

Spread of Herpes Simplex Virus to the Spinal Cord Is Independent of Spread to Dorsal Root Ganglia

Virus Diagnostics and Antiviral Therapy in Acute Retinal Necrosis (ARN)

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