Regulation of the Herpes Simplex Virus Latency-Associated Transcripts during Establishment of Latency in Sensory Neurons in Vitro

Smith, Roderic L.; Escudero, J M; Wilcox, Christine L.

doi:10.1006/viro.1994.1321

Cited by 27 publications

(35 citation statements)

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“…(up to 83% by day 21 p.i. ), as has been noted for other latency systems (29,48). As total neuron numbers were not determined in this experiment, we cannot rule out the possibility that the increase in LAP ϩ neurons over time results from selective loss of infected neurons in which the LAP is not active.…”

Section: Discussionmentioning

confidence: 70%

“…Further, reactivation is inducible in a controlled and uniform manner. Consistent with latency in vivo, no lytic cycle Ags are detectable, and in models utilizing primary neurons, transcription of LATs occurs (14,18,20,48,56). The best-characterized neuronal model system is that of Wilcox and coworkers (60)(61)(62), in which primary cultures of embryonic or neonatal rat sensory neurons are infected with wild-type virus in the presence of acyclovir (ACV).…”

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confidence: 68%

“…The best-characterized neuronal model system is that of Wilcox and coworkers (60)(61)(62), in which primary cultures of embryonic or neonatal rat sensory neurons are infected with wild-type virus in the presence of acyclovir (ACV). After several days, the cultures are free of infectious virus and LATs are detected in a large proportion of cells (14,48). In this and other neuron-based models, latency is dependent on the presence of nerve growth factor (NGF) and latent virus can be reactivated by NGF withdrawal, heat shock, or addition of activators of protein kinases (6,18,59,60).…”

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confidence: 94%

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Herpes Simplex Virus Type 1 Promoter Activity during Latency Establishment, Maintenance, and Reactivation in Primary Dorsal Root Neurons In Vitro

Arthur

Scarpini²,

Connor³

et al. 2001

J Virol

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A neonatal rat dorsal root ganglion-derived neuronal culture system has been utilized to study herpes simplex virus (HSV) latency establishment, maintenance, and reactivation. We present our initial characterization of viral gene expression in neurons following infection with replication-defective HSV recombinants carrying ␤-galactosidase and/or green fluorescent protein reporter genes under the control of lytic cycle-or latency-associated promoters. In this system lytic virus reporter promoter activity was detected in up to 58% of neurons 24 h after infection. Lytic cycle reporter promoters were shut down over time, and long-term survival of neurons harboring latent virus genomes was demonstrated. Latency-associated promoter-driven reporter gene expression was detected in neurons from early times postinfection and was stably maintained in up to 83% of neurons for at least 3 weeks. In latently infected cultures, silent lytic cycle promoters could be activated in up to 53% of neurons by nerve growth factor withdrawal or through inhibition of histone deacetylases by trichostatin A. We conclude that the use of recombinant viruses containing reporter genes, under the regulation of lytic and latency promoter control in neuronal cultures in which latency can be established and reactivation can be induced, is a potentially powerful system in which to study the molecular events that occur during HSV infection of neurons.A defining characteristic of herpesviruses is the ability to establish latent infections in their natural hosts. Herpes simplex virus (HSV) establishes latent infection in neurons of the peripheral nervous system, predominantly in sensory ganglia innervating the site of primary infection (25,53,58). Latent virus has the capacity to reactivate, which can give rise to a peripheral lesion in the dermatome relating to the affected ganglia (reviewed in reference 63). During latency the virus genome exists in a form lacking detectable free ends, consistent with the presence of episomal or concatemeric DNA (16,31,38). The latency-associated transcripts (LATs) are transcribed from a region within the repeats, mapping antisense to the IE110 gene, giving rise to a family of colinear RNAs (54; reviewed in reference 58). The LAT region is the only region of the genome that is abundantly transcribed during latency, giving rise to RNAs which are predominantly nuclear and consist of two highly abundant, nonpolyadenylated RNAs of 2 and 1.5 kb, termed major LATs. The precise mechanism of synthesis of major LATs is unclear (3), although there is compelling evidence that these transcripts are introns derived from a less abundant 8.5-kb polyadenylated precursor RNA termed a minor LAT (1,3,17,32,39,65,67). The function of the LATs is uncertain; investigations using mouse models have shown that LATs are not essential for the establishment or maintenance of a latent infection or for reactivation (5, 23, 52). There is evidence, however, indicating that LATs can increase the number of neurons in which latency is established. Fur...

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Section: Discussionmentioning

confidence: 70%

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confidence: 68%

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confidence: 94%

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Herpes Simplex Virus Type 1 Promoter Activity during Latency Establishment, Maintenance, and Reactivation in Primary Dorsal Root Neurons In Vitro

Arthur

Scarpini²,

Connor³

et al. 2001

J Virol

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“…6) predicts that on entry into the ganglion some neurons become infected and ultimately express LATs, whereas others succumb to productive infection. This model would be valid only if LATs were slower to accumulate in neurons on their way to establishing a latent infection than in neurons undergoing lytic infection, as has been suggested (27). The alternative model is that the virus spreads from neuron to neuron and in the course of this spread enters both permissive and nonpermissive cells.…”

Section: Discussionmentioning

confidence: 99%

“…LATs may appear in latently infected neurons after some delay as described in ref. 27. Model 2 predicts that virus spreads in neurons; some cells become productively infected and are destroyed, whereas others are committed to harbor latent virus.…”

Section: Methodsmentioning

confidence: 99%

HSV-1 gene expression from reactivated ganglia is disordered and concurrent with suppression of latency-associated transcript and miRNAs

Zhou

Roizman

2011

Proc. Natl. Acad. Sci. U.S.A.

110

132

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In cell cultures, HSV-1 replication is initiated by recruitment by virion protein 16 of transcriptional factors and histone-modifying enzymes to immediate early (α) gene promoters. HSV establishes latent infections characterized by suppression of viral gene expression except for latency-associated transcripts (LATs) and miRNAs. The latent virus reactivates in stressed neurons. A fundamental question is how reactivation initiates in the absence of virion protein 16. We report the following findings in the ganglion explant model. (i) Anti-nerve growth factor antibody accelerated the reactivation of latent virus. Viral mRNAs were detected as early as 9 h after explantation. (ii) After explantation the amounts of viral mRNAs increased whereas amounts of miRNAs and LATs decreased. The decrease in miRNAs and LATs required ongoing protein synthesis, raising the possibility that LAT and miRNAs were degraded by a viral gene product. (iii) The expression of viral genes in explanted ganglia was disordered rather than sequentially ordered as in infected cells in culture. These findings suggest that in reactivating ganglia gene expression is totally derepressed and challenge the current models in that establishment of or exit from latency could not be dependent on the suppression or activation of single or small clusters of viral genes. Finally, miRNAs and LATs reached peak levels 9-11 d after corneal inoculation, thus approximating the pattern of virus replication in these ganglia. These findings suggest that the patterns of accumulation of LATs and miRNAs reflect many different stages in the infection of neurons.T o initiate infection in cell culture and presumably also at the portal of entry into the body, the HSV-1 capsid delivers the DNA to the nucleus. Concurrently, virion protein 16 (VP16), a key viral protein packaged in the virion and delivered to the nucleus, recruits the cellular factors octamer-binding protein 1 (Oct1), host cell factor 1 (HCF1), lysine-specific demethylase 1 (LSD1), circadian locomotor output cycles kaput (CLOCK) histone acetyl transferase, and other transcriptional factors to initiate a cascade of viral gene expression that begins with immediate early (α) genes followed by early (β) and late (γ) genes (1-5). VP16 is encoded by a γ gene expressed late in infection (1). In all, the transcriptional program yields almost 100 different transcripts. In contrast, in latently infected neurons viral gene expression is limited to the latency-associated transcript (LAT) and approximately six or more miRNAs (6, 7). Given the requirement for VP16 to initiate viral replication in productively infected cells, the question arises as to how virus replication initiates in stressed neurons harboring latent virus. Among the many hypotheses, two stand out: That VP16 is expressed first or that in neurons α gene expression can ensue in the absence of VP16.Resolution of this problem requires analyses of the reactivation in ganglia under conditions that are physiologically similar to those that occur in vivo. In the st...

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The vasculopathy of varicella‐zoster virus encephalitis

Amlie‐Lefond

Kleinschmidt‐DeMasters

Mahalingam

et al. 1995

Annals of Neurology

123

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Varicella-zoster virus (VZV) encephalitis has become more prevalent in the era of acquired immunodeficiency syndrome and other immunosuppressive diseases and poses diagnostic and therapeutic challenges for clinicians, radiologists, and pathologists. Six cases studied at our institutions shed light on the patterns and pathogenesis of the disease. VZV encephalitis is predominantly a vasculopathy, involving small and large vessels, that generates seizures, mental changes, and focal deficits. Brain imaging reveals large and small ischemic or hemorrhagic infarcts, often both, of cortex and subcortical gray and white matter. Deep-seated white matter lesions often predominate and are ischemic and/or demyelinative, depending on the size of blood vessels involved and the amount of additional demyelination caused by infection of oligodendrocytes. The demyelinative lesions are smaller and less coalescent than those seen in progressive multifocal leukoencephalopathy.

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Regulation of the Herpes Simplex Virus Latency-Associated Transcripts during Establishment of Latency in Sensory Neurons in Vitro

Cited by 27 publications

References 0 publications

Herpes Simplex Virus Type 1 Promoter Activity during Latency Establishment, Maintenance, and Reactivation in Primary Dorsal Root Neurons In Vitro

Herpes Simplex Virus Type 1 Promoter Activity during Latency Establishment, Maintenance, and Reactivation in Primary Dorsal Root Neurons In Vitro

HSV-1 gene expression from reactivated ganglia is disordered and concurrent with suppression of latency-associated transcript and miRNAs

The vasculopathy of varicella‐zoster virus encephalitis

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