Characterization of an in vivo reactivation model of herpes simplex virus from mice trigeminal ganglia

Birmanns, Bettina; Reibstein, Israel; Steiner, Israel

doi:10.1099/0022-1317-74-11-2487

Cited by 20 publications

(7 citation statements)

References 28 publications

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“…Similar to the results of this study, it was previously shown that by 3 days p.i., CD8 ϩ T cells begin infiltrating the TG, peaking at 14 days (clear of virus by day 11 p.i. ), declining significantly after clearance of lytic infection, and persisting as latent virus (12,16,(27)(28)(29). In addition, in line with our results, it was previously shown that the level of PD-1 expression during the early stage of human hepatitis C virus (HCV) infection is significantly higher for subjects who progress to chronic HCV infection than for those who clear infection (30).…”

Section: Cd8supporting

confidence: 80%

Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

Mott

Allen

Zandian

et al. 2014

J Virol

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The latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1), CD8␣؉ dendritic cells (DCs), and programmed death 1 (PD-1) have all been implicated in the HSV-1 latency-reactivation cycle. It is not known, however, whether an interaction between LAT and CD8␣؉ A characteristic feature of infection with herpes simplex virus 1 (HSV-1) is the ability of the virus to establish latency in sensory neurons of an infected host (1-4). Individuals who have acquired a latent infection are subject to episodic recurrences and serve as permanent carriers who are intermittently infectious (5-7). The recurrences are caused by reactivation of the virus, which results in its transit back to the original site of infection (8, 9). More than 80 HSV-1 genes are expressed in neurons during lytic infection. This expression of HSV-1 genes is drastically curtailed during latency. Indeed, the latency-associated transcript (LAT) is the only gene product consistently detected in abundance during latency in infected mice, rabbits, and humans (1, 2, 4, 10, 11).Using LAT-expressing [LAT(ϩ)] and LAT-negative [LAT(Ϫ)] viruses, we recently demonstrated that the presence of LAT leads to the generation of dysfunctional T-cell responses in the trigeminal ganglia (TG) of latently infected mice (12). Both LAT expression and enhanced latency correlated with increased mRNA levels of CD8 and the inhibitory receptor programmed death 1 (PD-1) in the TG. These results suggested that TG that are latently infected with LAT(ϩ) virus contain both more CD8 ϩ T cells and more CD8ϩ T cells expressing the exhaustion marker, PD-1, than TG that are latently infected with LAT(Ϫ) virus. This was confirmed by flow cytometry analyses of expression of CD3, CD8, PD-1, HSV-1 gC, the gB 498 -505 -specific CD8 ϩ T-cell pentamer, interleukin-2 (IL-2), gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣). The functional significance of PD-1 and its ligands in HSV-1 latency was indicated by the significantly lower levels of HSV-1 latency in mice that were deficient in PD-1 or PD-1 ligand 1 (PD-L1) than in wild-type (WT) mice. The levels of HSV-1 latency were unaffected in PD-L2-deficent mice. We have also shown that latency is enhanced by immunization of infected WT mice with FMS-like tyrosine kinase 3 ligand (Flt3L) DNA, which increases the number of dendritic cells (DCs) (13,

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Section: Cd8supporting

confidence: 80%

Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

Mott

Allen

Zandian

et al. 2014

J Virol

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“…However, no evidence to prove a direct role for LATs in reactivation has so far been presented. The other possibility is that this gene(s) functions to promote the ability of HSV-1 to establish latent infection in neurons, increasing the pool of latently infected cells and indirectly improving reactivation ability (3,53). This is supported by the recent observation that HSV-1 reactivation efficacy correlated with its ability to establish latent infection in a high percentage of neurons (66).…”

Section: Discussionmentioning

confidence: 97%

Herpes Simplex Virus Type 1 Latency-Associated Transcripts Suppress Viral Replication and Reduce Immediate-Early Gene mRNA Levels in a Neuronal Cell Line

Mador¹,

Goldenberg²,

Cohen³

et al. 1998

J Virol

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During herpes simplex virus type 1 (HSV-1) latent infection in human dorsal root ganglia, limited viral transcription, which has been linked to HSV-1 reactivation ability, takes place. To study the involvement of this transcription in HSV-1 replication in neuronal cells and consequently in viral latency, we constructed stably transfected neuronal cell lines containing (i) the entire HSV-1 latency transcriptionally active DNA fragment, (ii) the same DNA sequence with deletions of the latency-associated transcript (LAT) promoters, or (iii) the DNA coding sequence of the LAT domain. Replication of HSV-1 or a LAT-negative mutant was markedly repressed in the LAT-expressing cells, a phenomenon mediated by the LATs. To study the mechanism responsible for this effect, we examined LAT influence upon expression of HSV-1 immediate-early (IE) genes ICP0, ICP4, and ICP27, by Northern blot analysis. Following infection of a LAT-expressing neuronal cell line with a LAT-negative mutant, the steady-state levels of all three IE mRNAs were reduced compared to those for control cells. Transient transfections into a neuronal cell line indicated that the LAT suppressive effect upon ICP0 mRNA was mediated directly and was not due to the LAT effect upon the ICP0 promoter. We therefore propose that the LATs may repress viral replication in neuronal cells by reducing IE gene mRNA levels and thus facilitate the establishment of HSV-1 latency in nervous tissue.

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“…This protein may also be involved in apoptosis of neurones that have been infected with HSV (28). The immune system contributes to the establishment of latency by suppressing infection and limiting the spread of the virus at synaptic junctions (29). Latency is accompanied by a chronic inflammatory process at an immunoprivileged site that seems to maintain viral latency and influence viral reactivation without leading to neuronal destruction (30).…”

Section: Pathogenesismentioning

confidence: 99%

Herpes Simplex Virus Type 1 infection: overview on relevant clinico‐pathological features*

Arduino

Porter

2007

J Oral Pathology Medicine

330

256

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Herpes Simplex Virus Type 1 (HSV-1) is a nuclear replicating enveloped virus, usually acquired through direct contact with infected lesions or body fluids (typically saliva). The prevalence of HSV-1 infection increases progressively from childhood, the seroprevalence being inversely related to socioeconomic background. Primary HSV-1 infections in children are either asymptomatic or following an incubation period of about 1 week gives rise to mucocutaneous vesicular eruptions. Herpetic gingivostomatitis typically affects the tongue, lips, gingival, buccal mucosa and the hard and soft palate. Most primary oro-facial HSV infection is caused by HSV-1, infection by HSV-2 is increasingly common. Recurrent infections, which occur at variable intervals, typically give rise to vesiculo-ulcerative lesions at mucocutaneous junctions particularly the lips (herpes labialis). Recurrent HSV-1 infection within the mouth is uncommon in otherwise healthy patients, although in immunocompromised patients, recurrent infection can be more extensive and/or aggressive. The diagnosis of common herpetic infection can usually be based upon the clinical history and presenting features. Confirmatory laboratory diagnosis is, however, required when patients are, or may be, immunocompromised.

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Characterization of an in vivo reactivation model of herpes simplex virus from mice trigeminal ganglia

Cited by 20 publications

References 28 publications

Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

Herpes Simplex Virus Type 1 Latency-Associated Transcripts Suppress Viral Replication and Reduce Immediate-Early Gene mRNA Levels in a Neuronal Cell Line

Herpes Simplex Virus Type 1 infection: overview on relevant clinico‐pathological features*

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