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

Harrison, Kelly S.; Zhu, Liqian; Thunuguntla, Prasanth; Jones, Clinton

doi:10.1371/journal.pone.0230870

Cited by 16 publications

(9 citation statements)

References 56 publications

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“…The Wnt/␤-catenin pathway is induced during BoHV-1 latency but repressed during DEX-induced reactivation (25,31,32). Mice latently infected with wild-type HSV-1 contain significantly more TG neurons that express ␤-catenin than those in an LAT-null mutant (33). Akt family members and the Wnt signaling pathway form a positive regulatory loop (34)(35)(36)(37)(38)(39), suggesting that these signaling pathways promote the maintenance of latency.…”

mentioning

confidence: 99%

Specific Akt Family Members Impair Stress-Mediated Transactivation of Viral Promoters and Enhance Neuronal Differentiation: Important Functions for Maintaining Latency

Zhao

Zhu

Wijesekera

et al. 2020

J Virol

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Neurotropic α-herpesvirinae subfamily members, bovine herpesvirus 1 (BoHV-1) and herpes simplex virus type 1 (HSV-1) for example, establish and maintain life-long latent infections in neurons. Following infection of ocular, oral, or nasal cavities, sensory neurons within trigeminal ganglia (TG) are an important site for latency. Certain external stressors can trigger reactivation from latency, in part, because activation of the glucocorticoid receptor (GR) stimulates productive infection and promoters that drive expression of key viral transcriptional regulators. The Akt serine/threonine protein kinase family is linked to maintaining latency. For example, Akt3 is detected in more TG neurons during BoHV-1 latency compared to reactivation and uninfected calves. Furthermore, Akt signaling correlates with maintaining HSV-1 latency in certain neuronal models of latency. Finally, an active Akt protein kinase is crucial for the ability of the HSV-1 latency associated transcript (LAT) to inhibit apoptosis in neuronal cell lines. Consequently, we hypothesized that viral and/or cellular factors impair stress-induced transcription and reduce the incidence of reactivation triggered by low levels of stress. New studies demonstrate Akt1 and Akt2, but not Akt3, significantly reduced GR-mediated transactivation of the BoHV-1 immediate early transcription unit 1 (IEtu1) promoter, HSV-1 infected cell protein 0 (ICP0) promoter, and mouse mammary tumor virus long terminal repeat. Akt3, but not Akt1 or Akt2, significantly enhanced neurite formation in mouse neuroblastoma cells, which correlates with repairing damaged neurons. These studies suggest unique biological properties of the three Akt family members promote the maintenance of latency in differentiated neurons. IMPORTANCE External stressful stimuli are known to increase the incidence of reactivation of alpha-herpesvirinae subfamily members. Activation of the glucocorticoid receptor (GR) by the synthetic corticosteroid dexamethasone stimulates bovine herpesvirus 1 (BoHV-1) and herpes simplex virus 1 (HSV-1) reactivation. Furthermore, GR and dexamethasone stimulate productive infection and promoters that drive expression of viral transcriptional regulators. These observations lead us to predict that stress-induced transcription is impaired by factors abundantly expressed during latency. Interestingly, activation of the Akt family of serine/threonine protein kinases is linked to maintenance of latency. New studies reveal Akt1 and Ak2, but not Akt3, impaired GR and dexamethasone mediated transactivation of the BoHV-1 immediate early transcription unit 1 and HSV-1 ICP0 promoters. Strikingly, Akt3, but not Akt1 or Akt2 stimulated neurite formation in mouse neuroblastoma cells, a requirement for neurogenesis. These studies provide insight into how Akt family members may promote the maintenance of life-long latency.

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mentioning

confidence: 99%

Specific Akt Family Members Impair Stress-Mediated Transactivation of Viral Promoters and Enhance Neuronal Differentiation: Important Functions for Maintaining Latency

Zhao

Zhu

Wijesekera

et al. 2020

J Virol

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“…In contrast, abortive reactivations are often lethal ( Doll et al, 2020 ). It is as yet also unclear whether transcriptional silencing is a direct result of the specific anatomy of the neurons, active shut down by viral factors, differential gene expression, signaling, protein localization, neuronal type, the terminally differentiated state of the neurons, or a variety of other factors ( Cabrera et al, 2018 ; Chen et al, 1997 ; Flowerdew et al, 2013 ; Hafezi et al, 2012 ; Harrison et al, 2020 ; Kobayashi et al, 2012b ; Kristie et al, 1999 ; Margolis et al, 2007 ; Maroui et al, 2016 ; Nicoll et al, 2016 ; Zhao et al, 2020 ). In summary, silencing at the establishment of latency is still the least understood stage in latency.…”

Section: The Hsv-1 Epigenomementioning

confidence: 99%

Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

Schang

Cortes

et al. 2021

Antiviral Research

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The ability to establish, and reactivate from, latent infections is central to the biology and pathogenesis of HSV-1. It also poses a strong challenge to antiviral therapy, as latent HSV-1 genomes do not replicate or express any protein to be targeted. Although the processes regulating the establishment and maintenance of, and reactivation from, latency are not fully elucidated, the current general consensus is that epigenetics play a major role. A unifying model postulates that whereas HSV-1 avoids or counteracts chromatin silencing in lytic infections, it becomes silenced during latency, silencing which is somewhat disrupted during reactivation. Many years of work by different groups using a variety of approaches have also shown that the lytic HSV-1 chromatin is distinct and has unique biophysical properties not shared with most cellular chromatin. Nonetheless, the lytic and latent viral chromatins are typically enriched in post translational modifications or histone variants characteristic of active or repressed transcription, respectively. Moreover, a variety of small molecule epigenetic modulators inhibit viral replication and reactivation from latency. Despite these successes in culture and animal models, it is not obvious how epigenetic modulation would be used in antiviral therapy if the same epigenetic mechanisms governed viral and cellular gene expression. Recent work has highlighted several important differences between the viral and cellular chromatins, which appear to be of consequence to their respective epigenetic regulations. In this review, we will discuss the distinctiveness of the viral chromatin, and explore whether it is regulated by mechanisms unique enough to be exploited in antiviral therapy.

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“… Reduces latency reactivation by approximately threefold [ 29 ] HSV-1 17Syn+ 17ΔPst Deletion of the 118664–118886 core promoter of LAT Reduces latency reactivation by approximately 3-fold [ 49 ] HSV-1 McKrae dLAT2903 LAT nucleotides (−)161 to +1667 Increased neurovirulence, and slightly more rapid reactivation [ 56 ] HSV-1 McKrae dLAT2903R Deletion of LAT1 (−161 to 1667) relative to the start of the primary 8.3-kb LAT Reactivate from latency is significantly reduced. [ 83 ] HSV-1 17syn+ LATRz-235 Deletions in the LAT promoter and portions of the 5ʹ exon coding region Resulting in a two- to threefold decreased reactivation [ 84 ] …”

Section: Application Of Hsv Lat Deletion Mutants In Hsv Vaccines and Ohsvsmentioning

confidence: 99%

“… 81 Other studies have shown that deletion of LAT can significantly reduce HSV reactivation. 31 , 82 , 83 In addition, studies have also shown that deletion of LAT can significantly reduce reactivation to about 33% of the normal level. 3 Similarly, partial LAT deletion mutation has been shown to lead to an approximately threefold increase of latency in the TG of wild-type mice infected with LAT(+) virus compared with mice infected with LAT(-) virus.…”

Section: Application Of Hsv Lat Deletion Mutants In Hsv Vaccines and Ohsvsmentioning

confidence: 99%

Multifunctional Non-Coding RNAs Mediate Latent Infection and Recurrence of Herpes Simplex Viruses

Zhang¹,

Zeng²,

Wang³

et al. 2021

IDR

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Herpes simplex viruses (HSVs) often cause latent infection for a lifetime, leading to repeated recurrence. HSVs have been engineered as oncolytic HSVs. The mechanism of the latent infection and recurrence remains largely unknown, which brings great challenges and limitations to eliminate HSVs in clinic and engineer safe oHSVs. Here, we systematically reviewed the latest development of the multi-step complex process of HSV latency and reactivation. Significantly, we first summarized the three HSV latent infection pathways, analyzed the structure and expression of the LAT1 and LAT2 of HSV-1 and HSV-2, proposed the regulation of LAT expression by four pathways, and dissected the function of LAT mediated by five LAT products of miRNAs, sRNAs, lncRNAs, sncRNAs and ORFs. We further analyzed that application of HSV LAT deletion mutants in HSV vaccines and oHSVs. Our review showed that deleting LAT significantly reduced the latency and reactivation of HSV, providing new ideas for the future development of safe and effective HSV therapeutics, vaccines and oHSVs. In addition, we proposed that RNA silencing or RNA interference may play an important role in HSV latency and reactivation, which is worth validating in future.

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

Cited by 16 publications

References 56 publications

Specific Akt Family Members Impair Stress-Mediated Transactivation of Viral Promoters and Enhance Neuronal Differentiation: Important Functions for Maintaining Latency

Specific Akt Family Members Impair Stress-Mediated Transactivation of Viral Promoters and Enhance Neuronal Differentiation: Important Functions for Maintaining Latency

Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

Multifunctional Non-Coding RNAs Mediate Latent Infection and Recurrence of Herpes Simplex Viruses

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