HSV1 latent transcription and non-coding RNA: A critical retrospective

Phelan, Dane; Barrozo, Enrico R.; Bloom, David C.

doi:10.1016/j.jneuroim.2017.03.002

Cited by 60 publications

(70 citation statements)

References 368 publications

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“…One of the clearest molecular signatures of HSV-1 latency is the accumulation of one or more stable introns formed by incomplete splicing of the latency-associated transcripts (LAT) (reviewed in [53]). In latency models, the abundance of the LAT RNAs increases during the establishment of latency [11] and can be detected in neurons of ganglia from the sacral, thoracic, and lumbar regions of recently deceased humans [54].…”

Section: Resultsmentioning

confidence: 99%

“…The ability to establish an infection in which the viral genome persists, but retain the capacity to reenter productive replication (i.e., reactivate), is a central tenet of accepted definitions of HSV-1 latency [66]. Infectious virus and GFP-Us11 expression, a marker of viral productive cycle (lytic) gene expression, were not detected after the establishment period, however the accumulation of LAT RNA, a molecular hallmark of latency, was readily observed [53]. Some of the next steps in characterizing this model will be to assess the structure of the viral episome during and after the establishment period and profile the expression of other latency-associated gene products such as the viral microRNAs [24].…”

Section: Discussionmentioning

confidence: 99%

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Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

et al. 2017

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Herpes simplex virus 1 (HSV-1) uses latency in peripheral ganglia to persist in its human host, however, recurrent reactivation from this reservoir can cause debilitating and potentially life-threatening disease. Most studies of latency use live-animal infection models, but these are complex, multilayered systems and can be difficult to manipulate. Infection of cultured primary neurons provides a powerful alternative, yielding important insights into host signaling pathways controlling latency. However, small animal models do not recapitulate all aspects of HSV-1 infection in humans and are limited in terms of the available molecular tools. To address this, we have developed a latency model based on human neurons differentiated in culture from an NIH-approved embryonic stem cell line. The resulting neurons are highly permissive for replication of wild-type HSV-1, but establish a non-productive infection state resembling latency when infected at low viral doses in the presence of the antivirals acyclovir and interferon-α. In this state, viral replication and expression of a late viral gene marker are not detected but there is an accumulation of the viral latency-associated transcript (LAT) RNA. After a six-day establishment period, antivirals can be removed and the infected cultures maintained for several weeks. Subsequent treatment with sodium butyrate induces reactivation and production of new infectious virus. Human neurons derived from stem cells provide the appropriate species context to study this exclusively human virus with the potential for more extensive manipulation of the progenitors and access to a wide range of preexisting molecular tools.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

et al. 2017

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“…Thus, there is a need to generate alternative viral genome annotations in which polycistronic gene arrays are collapsed into transcription units. Studies of herpesvirus latency or other low-abundance viral infections remain challenging, because viral mRNA abundance may often be below the level of detection in single cells and because viral markers of latency are not necessarily polyadenylated, as is the case for the stable intron derived from the herpes simplex virus (HSV) latency-associated transcript (37). Given the pace at which this field is progressing, many of these problems will likely be overcome and soon (30,38); however, caution must be exercised in the experimental design and interpretation, with an awareness that off-the-shelf bioinformatics solutions are rarely suited to examining host-virus interactions.…”

Section: Single-cell Rna Sequencingmentioning

confidence: 99%

Going the Distance: Optimizing RNA-Seq Strategies for Transcriptomic Analysis of Complex Viral Genomes

Depledge

Mohr

Wilson

2019

J Virol

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Transcriptome profiling has become routine in studies of many biological processes. However, the favored approaches such as short-read Illumina RNA sequencing are giving way to long-read sequencing platforms better suited to interrogating the complex transcriptomes typical of many RNA and DNA viruses. Here, we provide a guide-tailored to molecular virologists-to the ins and outs of viral transcriptome sequencing and discuss the strengths and weaknesses of the major RNA sequencing technologies as tools to analyze the abundance and diversity of the viral transcripts made during infection.

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“…More than 50% of adults in the United States are latently infected with herpes simplex virus 1 (HSV-1), reviewed in [1][2][3]. HSV-1 infections at the surface of the eye or oral cavity lead to life-long latent infections within sensory neurons of trigeminal ganglia (TG) as well as neurons within the central nervous system [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…Sporadic the life of an infected individual resulting in virus shedding at the periphery, which can trigger recurrent disease. In contrast to productive infection where more than 70 viral transcripts are readily detectable, including the latency-associated transcript (LAT), LAT is the only viral transcript abundantly expressed during latency [2,3]. Deleting LAT coding sequences or LAT promoter sequences reduce the efficiency of reactivation in latently infected rabbits and mice [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

et al. 2020

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When herpes simplex virus 1 (HSV-1) infection is initiated in the ocular, nasal, or oral cavity, sensory neurons within trigeminal ganglia (TG) become infected. Following a burst of viral transcription in TG neurons, lytic cycle viral genes are suppressed and latency is established. The latency-associated transcript (LAT) is the only viral gene abundantly expressed during latency, and LAT expression is important for the latency-reactivation cycle. Reactivation from latency is required for virus transmission and recurrent disease, including encephalitis. The Wnt/β-catenin signaling pathway is differentially expressed in TG during the bovine herpesvirus 1 latency-reactivation cycle. Hence, we hypothesized HSV-1 regulates the Wnt/β-catenin pathway and promotes maintenance of latency because this pathway enhances neuronal survival and axonal repair. New studies revealed β-catenin was expressed in significantly more TG neurons during latency compared to TG from uninfected mice or mice latently infected with a LAT -/mutant virus. When TG explants were incubated with media containing dexamethasone to stimulate reactivation, significantly fewer β-cate-nin+ TG neurons were detected. Conversely, TG explants from uninfected mice or mice latently infected with a LAT -/mutant increased the number of β-catenin+ TG neurons in the presence of DEX relative to samples not treated with DEX. Impairing Wnt signaling with small molecule antagonists reduced virus shedding during explant-induced reactivation. These studies suggested β-catenin was differentially expressed during the latency-reactivation cycle, in part due to LAT expression. OPEN ACCESS Citation: Harrison KS, Zhu L, Thunuguntla P, Jones C (2020) Herpes simplex virus 1 regulates βcatenin expression in TG neurons during the latency-reactivation cycle. PLoS ONE 15(3): e0230870. https://doi.

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HSV1 latent transcription and non-coding RNA: A critical retrospective

Cited by 60 publications

References 368 publications

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

Going the Distance: Optimizing RNA-Seq Strategies for Transcriptomic Analysis of Complex Viral Genomes

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

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