Submit to Viruses Review for Viruses Propose a Special Issue

Journal Browser

► Journal Browser

Herpesvirus Latency

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 27255

Share This Special Issue

Special Issue Editor

Prof. Dr. Clinton Jones

E-Mail Website
Guest Editor

Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA
Interests: alpha-herpesviruses (BoHV-1 and HSV-1); latency; virus-host interactions; viral gene expression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There are more than a 100 Herpesviridae family members that infect humans or animals. A noteworthy biological property of all known herpesviruses is their ability to establish a lifelong latent infection in their respective hosts. In contrast to productive infection, viral gene expression is restricted, and virus shedding is not readily detected during latency. Periodically, reactivation from latency occurs, which is essential for virus transmission. Furthermore, reactivation from latency can culminate in serious recurrent diseases. Although the latency–reactivation cycle has been studied for many herpesvirus family members, there are many aspects of these complex virus-host interactions that are poorly understood. This Special Issue is focused on exciting and new studies germane to understanding the latency–reactivation cycle, the role the immune system plays in this process, and how cellular factors mediate the latency–reactivation cycle.

Prof. Dr. Clinton Jones
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

herpesviruses
latent infections
viral genes expressed during latency
reactivation from latency
models of latency
immune control of latency
cellular factors that mediate the latency reactivation cycle

Published Papers (12 papers)

Download All Papers

Research

Jump to: Review, Other

18 pages, 3292 KiB

Open AccessArticle

The Virus-Induced Upregulation of the miR-183/96/182 Cluster and the FoxO Family Protein Members Are Not Required for Efficient Replication of HSV-1

by Andreja Zubković, Ines Žarak, Ivana Ratkaj, Filip Rokić, Maja Jekić, Marina Pribanić Matešić, Ricardo Lebrón, Cristina Gómez-Martín, Berislav Lisnić, Vanda Juranić Lisnić, Stipan Jonjić, Dongli Pan, Oliver Vugrek, Michael Hackenberg and Igor Jurak

Viruses 2022, 14(8), 1661; https://0-doi-org.brum.beds.ac.uk/10.3390/v14081661 - 28 Jul 2022

Cited by 2 | Viewed by 1696

Abstract

Herpes simplex virus 1 (HSV-1) expresses a large number of miRNAs, and their function is still not completely understood. In addition, HSV-1 has been found to deregulate host miRNAs, which adds to the complexity of the regulation of efficient virus replication. In this study, we comprehensively addressed the deregulation of host miRNAs by massive-parallel sequencing. We found that only miRNAs expressed from a single cluster, miR-183/96/182, are reproducibly deregulated during productive infection. These miRNAs are predicted to regulate a great number of potential targets involved in different cellular processes and have only 33 shared targets. Among these, members of the FoxO family of proteins were identified as potential targets for all three miRNAs. However, our study shows that the upregulated miRNAs do not affect the expression of FoxO proteins, moreover, these proteins were upregulated in HSV-1 infection. Furthermore, we show that the individual FoxO proteins are not required for efficient HSV-1 replication. Taken together, our results indicate a complex and redundant response of infected cells to the virus infection that is efficiently inhibited by the virus. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

15 pages, 4042 KiB

Open AccessArticle

Independent Cis-Regulatory Modules within the Herpes Simplex Virus 1 Infected Cell Protein 0 (ICP0) Promoter Are Transactivated by Krüppel-like Factor 15 and Glucocorticoid Receptor

by Nishani Wijesekera, Nicholas Hazell and Clinton Jones

Viruses 2022, 14(6), 1284; https://0-doi-org.brum.beds.ac.uk/10.3390/v14061284 - 13 Jun 2022

Cited by 6 | Viewed by 1921

Abstract

A corticosteroid antagonist impairs Herpes Simplex Virus 1 (HSV-1) productive infection and explant-induced reactivation from latency, suggesting corticosteroids and the glucocorticoid receptor (GR) mediate certain aspects of these complex virus–host interactions. GR-hormone complexes regulate transcription positively and negatively, in part, by binding GR response elements (GREs). Recent studies revealed infected cell protein 0 (ICP0), ICP4, and ICP27 promoter/cis-regulatory modules (CRMs) are cooperatively transactivated by GR and Krüppel-like factor 15 (KLF15), which forms a feed-forward transcription loop. We hypothesized the ICP0 promoter contains independent CRMs that are transactivated by GR, KLF15, and the synthetic corticosteroid dexamethasone (DEX). This hypothesis is based on the finding that the ICP0 promoter contains multiple transcription factor binding sites, and GR and KLF15 cooperatively transactivate the full-length ICP0 promoter. ICP0 promoter sequences spanning −800 to −635 (fragment A) were efficiently transactivated by GR, KLF15, and DEX in monkey kidney cells (Vero), whereas GR and DEX significantly enhanced promoter activity in mouse neuroblastoma cells (Neuro-2A). Furthermore, ICP0 fragment B (−458 to −635) was efficiently transactivated by GR, KLF15, and DEX in Vero cells, but not Neuro-2A cells. Finally, fragment D (−232 to −24) was transactivated significantly in Vero cells by GR, KLF15, and DEX, whereas KLF15 and DEX were sufficient for transactivation in Neuro-2A cells. Collectively, these studies revealed efficient transactivation of three independent CRMs within the ICP0 promoter by GR, KLF15, and/or DEX. Finally, GC-rich sequences containing specificity protein 1 (Sp1) binding sites were essential for transactivation. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

10 pages, 1040 KiB

Open AccessArticle

Design of a US28 ORF Deletion Virus in a Temperature-Sensitive Cytomegalovirus Strain Fails to Promote Lytic Replication in Hematopoietic Cells

by Benjamin A. Krishna, Amanda B. Wass, Eain A. Murphy and Christine M. O’Connor

Viruses 2022, 14(6), 1280; https://0-doi-org.brum.beds.ac.uk/10.3390/v14061280 - 12 Jun 2022

Cited by 1 | Viewed by 1460

Abstract

Human cytomegalovirus (CMV) is a ubiquitous pathogen that latently resides in hematopoietic cells. Latently infected individuals with dysfunctional immune systems often experience CMV reactivation, which can cause devastating disease and mortality. While factors dictating the balance between latency and reactivation are not completely understood, CMV US28 is required for maintaining latent infection, and viral mutants that alter US28 function result in a lytic-like, rather than latent, infection in hematopoietic cells. In turn, viral lytic factors alter the host cell, making it challenging to characterize the US28-specific changes in the cellular milieu. To circumvent this, we generated a temperature-sensitive TB40/E recombinant virus, TB40/EgfpC510G (tsC510G), into which we engineered an amino acid change at position 510 (C510G) of IE2, as previously described in the CMV Towne strain. Using tsC510G, we then deleted the US28 ORF, termed tsC510G-US28Δ. Consistent with previous findings, tsC510G-US28Δ fails to undergo latency in Kasumi-3 cells at the permissive temperature. However, parallel cultures maintained at the non-permissive temperature showed a significant reduction in infectious center frequency, as measured by limiting dilution assay. Thus, we generated a new US28 mutant virus for use as a tool to study US28-specific changes in latently infected hematopoietic cells in the absence of induced lytic replication. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

21 pages, 2778 KiB

Open AccessArticle

Stress Hormones Epinephrine and Corticosterone Selectively Reactivate HSV-1 and HSV-2 in Sympathetic and Sensory Neurons

by Poorna Goswami, Angela M. Ives, Amber R. N. Abbott and Andrea S. Bertke

Viruses 2022, 14(5), 1115; https://0-doi-org.brum.beds.ac.uk/10.3390/v14051115 - 23 May 2022

Cited by 7 | Viewed by 2563

Abstract

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency in sensory and autonomic neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is strongly associated with HSV recurrences in humans and animal models. However, the mechanisms through which stress hormones act on the latent virus to cause reactivation are unknown. We show that the stress hormones epinephrine (EPI) and corticosterone (CORT) induce HSV-1 reactivation selectively in sympathetic neurons, but not sensory or parasympathetic neurons. Activation of multiple adrenergic receptors is necessary for EPI-induced HSV-1 reactivation, while CORT requires the glucocorticoid receptor. In contrast, CORT, but not EPI, induces HSV-2 reactivation in both sensory and sympathetic neurons through either glucocorticoid or mineralocorticoid receptors. Reactivation is dependent on different transcription factors for EPI and CORT, and coincides with rapid changes in viral gene expression, although genes differ for HSV-1 and HSV-2, and temporal kinetics differ for EPI and CORT. Thus, stress-induced reactivation mechanisms are neuron-specific, stimulus-specific and virus-specific. These findings have implications for differences in HSV-1 and HSV-2 recurrent disease patterns and frequencies, as well as development of targeted, more effective antivirals that may act on different responses in different types of neurons. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

18 pages, 2143 KiB

Open AccessArticle

Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo

by Pankaj Singh, Matthew F. Collins, Richard N. Johns, Kayley A. Manuel, Ziyun A. Ye, David C. Bloom and Donna M. Neumann

Viruses 2022, 14(5), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/v14050909 - 27 Apr 2022

Cited by 3 | Viewed by 1905

Abstract

HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5′exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

10 pages, 2534 KiB

Open AccessArticle

Efficacy of an HSV-1 Neuro-Attenuated Vaccine in Mice Is Reduced by Preventing Viral DNA Replication

by Hong Wang, David J. Davido, Heba H. Mostafa and Lynda A. Morrison

Viruses 2022, 14(5), 869; https://0-doi-org.brum.beds.ac.uk/10.3390/v14050869 - 22 Apr 2022

Cited by 1 | Viewed by 1765

Abstract

We previously isolated an HSV-1 mutant, KOS-NA, that contains two non-synonymous mutations in UL39. One of the mutations, resulting in an R950H amino acid substitution in ICP6, renders KOS-NA severely neuro-attenuated and significantly reduces HSV-1 latency. Vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated eye diseases even at a very low immunizing dose, indicating its utility as a vaccine scaffold. Because KOS-NA contains a neuro-attenuating mutation in a single gene, we sought to improve its safety by deleting a portion of the UL29 gene whose protein product, ICP8, is essential for viral DNA replication. Whereas KOS-NA reduced replication of HSV-1 challenge virus in the corneal epithelium and protected mice against blepharitis and keratitis induced by the challenge virus, KOS-NA/8- and an ICP8- virus were significantly less efficacious except at higher doses. Our results suggest that the capacity to replicate, even at significantly reduced levels compared with wild-type HSV-1, may be an important feature of an effective vaccine. Means to improve safety of attenuated viruses as vaccines without compromising efficacy should be sought. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

10 pages, 1430 KiB

Open AccessArticle

VZV Infection of Primary Human Adrenal Cortical Cells Produces a Proinflammatory Environment without Cell Death

by Christy S. Niemeyer, Teresa Mescher, Andrew N. Bubak, Eva M. Medina, James E. Hassell, Jr. and Maria A. Nagel

Viruses 2022, 14(4), 674; https://0-doi-org.brum.beds.ac.uk/10.3390/v14040674 - 25 Mar 2022

Cited by 4 | Viewed by 2273

Abstract

Virus infection of adrenal glands can disrupt secretion of mineralocorticoids, glucocorticoids, and sex hormones from the cortex and catecholamines from the medulla, leading to a constellation of symptoms such as fatigue, dizziness, weight loss, nausea, and muscle and joint pain. Specifically, varicella zoster virus (VZV) can produce bilateral adrenal hemorrhage and adrenal insufficiency during primary infection or following reactivation. However, the mechanisms by which VZV affects the adrenal glands are not well-characterized. Herein, we determined if primary human adrenal cortical cells (HAdCCs) infected with VZV support viral replication and produce a proinflammatory environment. Quantitative PCR showed VZV DNA increasing over time in HAdCCs, yet no cell death was seen at 3 days post-infection by TUNEL staining or Western Blot analysis with PARP and caspase 9 antibodies. Compared to conditioned supernatant from mock-infected cells, supernatant from VZV-infected cells contained significantly elevated IL-6, IL-8, IL-12p70, IL-13, IL-4, and TNF-α. Overall, VZV can productively infect adrenal cortical cells in the absence of cell death, suggesting that these cells may be a potential reservoir for ongoing viral replication and proinflammatory cytokine production, leading to chronic adrenalitis and dysfunction. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

16 pages, 3016 KiB

Open AccessArticle

A Viral Long Non-Coding RNA Protects against Cell Death during Human Cytomegalovirus Infection of CD14+ Monocytes

by Marianne R. Perera, Kathryn L. Roche, Eain A. Murphy and John H. Sinclair

Viruses 2022, 14(2), 246; https://0-doi-org.brum.beds.ac.uk/10.3390/v14020246 - 26 Jan 2022

Cited by 6 | Viewed by 3062

Abstract

Long non-coding RNA β2.7 is the most highly transcribed viral gene during latent human cytomegalovirus (HCMV) infection. However, as yet, no function has ever been ascribed to β2.7 during HCMV latency. Here we show that β2.7 protects against apoptosis induced by high levels of reactive oxygen species (ROS) in infected monocytes, which routinely support latent HCMV infection. Monocytes infected with a wild-type (WT) virus, but not virus deleted for the β2.7 gene (Δβ2.7), are protected against mitochondrial stress and subsequent apoptosis. Protected monocytes display lower levels of ROS and additionally, stress-induced death in the absence of β2.7 can be reversed by an antioxidant which reduces ROS levels. Furthermore, we show that infection with WT but not Δβ2.7 virus results in strong upregulation of a cellular antioxidant enzyme, superoxide dismutase 2 (SOD2) in CD14+ monocytes. These observations identify a role for the β2.7 viral transcript, the most abundantly expressed viral RNA during latency but for which no latency-associated function has ever been ascribed, and demonstrate a novel way in which HCMV protects infected monocytes from pro-death signals to optimise latent carriage. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

Review

Jump to: Research, Other

19 pages, 3155 KiB

Open AccessReview

MicroRNA Regulation of Human Herpesvirus Latency

by Siyu Chen, Yue Deng and Dongli Pan

Viruses 2022, 14(6), 1215; https://0-doi-org.brum.beds.ac.uk/10.3390/v14061215 - 02 Jun 2022

Cited by 10 | Viewed by 2616

Abstract

Herpesviruses are ubiquitous human pathogens. After productive (lytic) infection, all human herpesviruses are able to establish life-long latent infection and reactivate from it. Latent infection entails suppression of viral replication, maintenance of the viral genome in infected cells, and the ability to reactivate. Most human herpesviruses encode microRNAs (miRNAs) that regulate these processes during latency. Meanwhile, cellular miRNAs are hijacked by herpesviruses to participate in these processes. The viral or cellular miRNAs either directly target viral transcripts or indirectly affect viral infection through host pathways. These findings shed light on the molecular determinants that control the lytic-latent switch and may lead to novel therapeutics targeting latent infection. We discuss the multiple mechanisms by which miRNAs regulate herpesvirus latency, focusing on the patterns in these mechanisms. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

7 pages, 239 KiB

Open AccessReview

Effect of Routine Varicella Immunization on the Epidemiology and Immunogenicity of Varicella and Shingles

by Naruhito Otani, Masayuki Shima, Takuma Yamamoto and Toshiomi Okuno

Viruses 2022, 14(3), 588; https://0-doi-org.brum.beds.ac.uk/10.3390/v14030588 - 12 Mar 2022

Cited by 5 | Viewed by 3310

Abstract

Varicella-zoster virus (VZV) causes varicella as a primary infection and remains latent in the ganglia until it becomes reactivated to cause herpes zoster. Individuals with varicella develop adaptive humoral and cell-mediated immunity. Compromised cell-mediated immunity is thought to contribute to the development of herpes zoster. Recent evidence suggests that changes in the epidemiology of varicella have affected the epidemiology of herpes zoster. The incidence of herpes zoster is higher in older adults; thus, the herpes zoster vaccine is recommended for older adults. However, the incidence of herpes zoster is expected to rise among younger individuals; hence, vaccination with the varicella vaccine should also be considered in younger adults. In order to determine the need for vaccination in different populations, it is important to establish methods to accurately assess the activity of cell-mediated immunity and humoral immunity. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

Other

Jump to: Research, Review

11 pages, 1909 KiB

Open AccessBrief Report

Impact of Host Telomere Length on HHV-6 Integration

by Darren J. Wight, Giulia Aimola, Georg Beythien, Louis Flamand and Benedikt B. Kaufer

Viruses 2022, 14(9), 1864; https://0-doi-org.brum.beds.ac.uk/10.3390/v14091864 - 24 Aug 2022

Viewed by 1430

Abstract

Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

► Show Figures

Figure 1

15 pages, 291 KiB

Open AccessOpinion

Fraternal Twins: The Enigmatic Role of the Immune System in Alphaherpesvirus Pathogenesis and Latency and Its Impacts on Vaccine Efficacy

by Barry T. Rouse and D. Scott Schmid

Viruses 2022, 14(5), 862; https://doi.org/10.3390/v14050862 - 21 Apr 2022

Cited by 4 | Viewed by 1884

Abstract

Although the establishment, maintenance and reactivation from alphaherpesvirus latency is far from fully understood, some things are now manifestly clear: Alphaherpesvirus latency occurs in neurons of the peripheral nervous system and control of the process is multifactorial and complex. This includes components of the immune system, contributions from non-neuronal cells surrounding neurons in ganglia, specialized nucleic acids and modifications to the viral DNA to name some of the most important. Efficacious vaccines have been developed to control both acute varicella and zoster, the outcome of reactivation, but despite considerable effort vaccines for acute herpes simplex virus (HSV) infection or reactivated lesions have thus far failed to materialize despite considerable effort. Given the relevance of the immune system to establish and maintain HSV latency, a vaccine designed to tailor the HSV response to maximize the activity of components most critical for controlling reactivated infection might limit the severity of recurrences and hence reduce viral transmission. In this review, we discuss the current understanding of immunological factors that contribute to HSV and VZV latency, identify differences between varicella-zoster virus (VZV) and HSV that could explain why vaccines have been valuable at controlling VZV disease but not HSV, and finish by outlining possible strategies for developing effective HSV vaccines. Full article

(This article belongs to the Special Issue Herpesvirus Latency)

Journal Menu

Journal Browser

Herpesvirus Latency

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (12 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI