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Viruses
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Recent Advances in Herpesviruses Research: What's in the Pipeline?
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Recent Advances in Herpesviruses Research: What's in the Pipeline?

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

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 59187

Special Issue Editor

Dr. Sherif T. S. Hassan

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Guest Editor
Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic
Interests: infectious diseases; pharmacology and toxicology of natural products; analytical methods for isolation and identification of natural products; molecular mechanisms of pharmacological action; pediatric infectious diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, infection with herpesviruses has become a global concern due to its great threat to public health. Herpesviruses are infectious agents belonging to the virus family Herpesviridae that cause latent and lytic infections in humans and in a wide range of animals. There are eight herpesvirus types currently known to infect humans, including Herpes simplex viruses (HSV-1 and HSV-2), varicella-zoster virus, Epstein–Barr virus, human herpesvirus 6 (variants A and B), human herpesvirus 7, Kaposi's sarcoma-associated herpesvirus, and human cytomegalovirus. Although the efficacy of the treatments of herpesviruses infection has improved during the past two decades, the increasing use of antiviral drugs has resulted in drug resistance, which, in turn, has switched researchers’ attention toward more effective therapeutic strategies based on novel antiviral drugs associated with decreased resistance, less undesirable side effects, and various mechanisms of action. This Special Issue aims to shed light on the recent advances in both preclinical and clinical studies on herpesviruses and in therapeutic developments in the treatment of herpesviruses infection.

Dr. Sherif T. S. Hassan
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 infection
  • antiviral therapeutics
  • resistance
  • vaccine development
  • preclinical and clinical studies
  • host–pathogen interactions
  • viral pathogenesis

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 4189 KiB  
Editorial
Shedding Light on the Effect of Natural Anti-Herpesvirus Alkaloids on SARS-CoV-2: A Treatment Option for COVID-19
by Sherif T. S. Hassan
Viruses 2020, 12(4), 476; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040476 - 23 Apr 2020
Cited by 20 | Viewed by 5579
Abstract
The whole world is currently facing an unseen enemy, called coronavirus disease 2019 (COVID-19), which is causing a global pandemic. This disease is caused by a novel single-stranded enveloped RNA virus, known as the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Although huge efforts [...] Read more.
The whole world is currently facing an unseen enemy, called coronavirus disease 2019 (COVID-19), which is causing a global pandemic. This disease is caused by a novel single-stranded enveloped RNA virus, known as the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Although huge efforts are being made to produce effective therapies to combat this disease, it continues to be one of the greatest challenges in medicine. There is no doubt that herpesviruses are one of the most important viruses that infect humans and animals, and infections induced by these pathogens have developed into a great threat to public health. According to the currently available evidence, the correlation between herpesviruses and coronaviruses is limited to the induced complications following the infections. For instance, the inflammation that is induced at the sites of infection could tie these viruses to each other in a relationship. Another example, bovine herpesvirus 1, which is an important pathogen of cattle, can cause a severe respiratory infection; the same way in which SARS-CoV-2 affects humans. Considering the current circumstances related to the COVID-19 crisis, this editorial paper, which belongs to the Special Issue “Recent Advances in Herpesviruses Research: What’s in the Pipeline?” aims to draw attention to some natural anti-herpesvirus alkaloid compounds, which have recently been proven to have excellent inhibitory efficacy against SARS-CoV-2 replication. Thus, this special focus is an attempt to hunt down various treatment options to combat COVID-19 based on repurposing drugs that are known to have multiple antiviral properties, including against herpesvirus. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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Research

Jump to: Editorial, Review

11 pages, 2902 KiB  
Article
KSHV ORF59 and PAN RNA Recruit Histone Demethylases to the Viral Chromatin during Lytic Reactivation
by Kayla Hiura, Roxanne Strahan, Timsy Uppal, Brian Prince, Cyprian C. Rossetto and Subhash C. Verma
Viruses 2020, 12(4), 420; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040420 - 09 Apr 2020
Cited by 12 | Viewed by 3300
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes multiple malignancies in immunocompromised individuals. KSHV primarily establishes a lifelong latency in infected humans during which only a subset of viral genes is expressed while most of the viral genome remains transcriptionally silent with condensed chromatin. However, during [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes multiple malignancies in immunocompromised individuals. KSHV primarily establishes a lifelong latency in infected humans during which only a subset of viral genes is expressed while most of the viral genome remains transcriptionally silent with condensed chromatin. However, during the lytic phase, the viral genome undergoes dramatic changes in chromatin landscape leading to a transcriptionally active state with the expression of most of the viral genes and production of progeny virions. Multiple cellular and viral factors influence the epigenetic gene regulation and transitioning of virus from latency to the lytic state. We have earlier shown that KSHV ORF59, viral processivity factor, binds to a protein arginine methyl transferase 5 (PRMT5) to alter the histone arginine methylation during reactivation. Additionally, ORF59 has been shown to interact with most abundantly expressed KSHV long noncoding polyadenylated nuclear RNA (PAN RNA), which associates with the viral epigenome during reactivation. Interestingly, PAN RNA interacts with UTX and JMJD3, cellular H3K27me3 demethylases, and removes the repressive marks on the chromatin. In this study, we report that the recruitment of histone demethylases to the viral chromatin is facilitated by the expression of ORF59 protein and PAN RNA. Using biochemical and localization assays including co-immunoprecipitation and immunofluorescence, we demonstate ORF59 localizes with UTX and JMJD3. Our results confirm that PAN RNA enhances the interaction of ORF59 with the chromatin modifying enzymes UTX and JMJD3. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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17 pages, 2794 KiB  
Article
The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases
by Eric S. Pringle, Jaime Wertman, Nicole Melong, Andrew J. Coombs, Andrew L. Young, David O’Leary, Chansey Veinotte, Carolyn-Ann Robinson, Michael N. Ha, Graham Dellaire, Todd E. Druley, Craig McCormick and Jason N. Berman
Viruses 2020, 12(1), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/v12010012 - 20 Dec 2019
Cited by 12 | Viewed by 4516
Abstract
Kaposi’s sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic, but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of [...] Read more.
Kaposi’s sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic, but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of latently infected B lymphocytes, and supported by pro-inflammatory cytokines and angiogenic factors produced by cells that succumb to lytic viral replication. Here, we report the development of the first in vivo model for a virally induced lymphoma in zebrafish, whereby KSHV-infected PEL tumor cells engraft and proliferate in the yolk sac of zebrafish larvae. Using a PEL cell line engineered to produce the viral lytic switch protein RTA in the presence of doxycycline, we demonstrate drug-inducible reactivation from KSHV latency in vivo, which enabled real-time observation and evaluation of latent and lytic phases of KSHV infection. In addition, we developed a sensitive droplet digital PCR method to monitor latent and lytic viral gene expression and host cell gene expression in xenografts. The zebrafish yolk sac is not well vascularized, and by using fluorogenic assays, we confirmed that this site provides a hypoxic environment that may mimic the microenvironment of some human tumors. We found that PEL cell proliferation in xenografts was dependent on the host hypoxia-dependent translation initiation factor, eukaryotic initiation factor 4E2 (eIF4E2). This demonstrates that the zebrafish yolk sac is a functionally hypoxic environment, and xenografted cells must switch to dedicated hypoxic gene expression machinery to survive and proliferate. The establishment of the PEL xenograft model enables future studies that exploit the innate advantages of the zebrafish as a model for genetic and pharmacologic screens. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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11 pages, 1508 KiB  
Communication
Highlighting of a LAGLIDADG and a Zing Finger Motifs Located in the pUL56 Sequence Crucial for HCMV Replication
by Gaëtan Ligat, Anthony Couvreux, Raphaël Cazal, Sophie Alain and Sébastien Hantz
Viruses 2019, 11(12), 1093; https://0-doi-org.brum.beds.ac.uk/10.3390/v11121093 - 26 Nov 2019
Cited by 4 | Viewed by 2810
Abstract
The human cytomegalovirus (HCMV) terminase complex is part of DNA-packaging machinery that delivers a unit-length genome into a procapsid. Sequence comparison of herpesvirus homologs allowed us to identify a potential LATLNDIERFL and zinc finger pattern in N-terminal part of pUL56. Recombinant viruses were [...] Read more.
The human cytomegalovirus (HCMV) terminase complex is part of DNA-packaging machinery that delivers a unit-length genome into a procapsid. Sequence comparison of herpesvirus homologs allowed us to identify a potential LATLNDIERFL and zinc finger pattern in N-terminal part of pUL56. Recombinant viruses were generated with specific serine or alanine substitutions in these putative patterns. We identified a LATLNDIERFL pattern characteristic of LAGLIDADG homing endonucleases and a metal-binding pattern involving the cysteine and histidine residues C191-X2-C194-X22-C217-X-H219 (CCCH) close to the region conferring letermovir resistance. These patterns are crucial for viral replication, suggesting that they are essential for pUL56 structure and function. Thus, these patterns represent potential targets for the development of new antivirals such as small molecules or peptides and may allow to better understand the letermovir mechanism of action. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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Graphical abstract

13 pages, 3044 KiB  
Communication
Role of Herpes Simplex Envelope Glycoprotein B and Toll-Like Receptor 2 in Ocular Inflammation: An Ex Vivo Organotypic Rabbit Corneal Model
by Andreana Marino, Simona Pergolizzi, Francesco Cimino, Eugenia Rita Lauriano, Antonio Speciale, Valeria D’Angelo, Mariaconcetta Sicurella, Rafaela Argnani, Roberto Manservigi and Peggy Marconi
Viruses 2019, 11(9), 819; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090819 - 04 Sep 2019
Cited by 15 | Viewed by 3701
Abstract
It has been recently reported, using in vitro studies, that the herpes simplex virus 1 (HSV-1) encoded envelope glycoprotein B (gB1) interacts with cell surface toll-like receptor 2 (TLR2) and induces the secretion of interleukin-8 (IL8), a representative marker of inflammatory cytokine activation. [...] Read more.
It has been recently reported, using in vitro studies, that the herpes simplex virus 1 (HSV-1) encoded envelope glycoprotein B (gB1) interacts with cell surface toll-like receptor 2 (TLR2) and induces the secretion of interleukin-8 (IL8), a representative marker of inflammatory cytokine activation. The purpose of this study is to investigate the role of gB1 in activating host inflammatory responses by using a secreted form of gB1 (gB1s) and an ex vivo organotypic rabbit corneal model. Abraded corneas exposed to gB1s alone or to the recombinant protein mixed with anti gB polyclonal antibody were cultured in an air–liquid interface. The corneas exposed to gB1s show the appearance of mydriasis and high levels of TLR2 and IL-8 mRNAs transcripts were detected in the superficial layer of corneal epithelial cells. Histological stain and immunohistochemical analyses revealed morphological changes in the epithelium of the treated corneas and variations in expression and localization of TLR2. Collectively these findings provide new insight into the pathogenesis of HSV-1 ocular infection by demonstrating the leading role of gB in activating an inflammatory response and in the appearance of mydriasis, a sign of HSV-1 anterior uveitis. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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12 pages, 1545 KiB  
Article
Cyprinid herpesvirus 3 Evolves In Vitro through an Assemblage of Haplotypes that Alternatively Become Dominant or Under-Represented
by Sandro Klafack, Anna-Sophie Fiston-Lavier, Sven M. Bergmann, Saliha Hammoumi, Lars Schröder, Walter Fuchs, Angela Lusiastuti, Pei-Yu Lee, Sarahi Vega Heredia, Master student consortium, Anne-Sophie Gosselin-Grenet and Jean-Christophe Avarre
Viruses 2019, 11(8), 754; https://doi.org/10.3390/v11080754 - 15 Aug 2019
Cited by 7 | Viewed by 5329
Abstract
Viruses are able to evolve in vitro by mutations after serial passages in cell cultures, which can lead to either a loss, or an increase, of virulence. Cyprinid herpesvirus 3 (CyHV-3), a 295-kb double-stranded DNA virus, is the etiological agent of the koi [...] Read more.
Viruses are able to evolve in vitro by mutations after serial passages in cell cultures, which can lead to either a loss, or an increase, of virulence. Cyprinid herpesvirus 3 (CyHV-3), a 295-kb double-stranded DNA virus, is the etiological agent of the koi herpesvirus disease (KHVD). To assess the influence of serial passages, an isolate of CyHV-3 (KHV-T) was passaged 99 times onto common carp brain (CCB) cells, and virus virulence was evaluated during passages through the experimental infections of common carp. After 78 CCB passages, the isolate was much less virulent than the original form. A comparative genomic analysis of these three forms of KHV-T (P0, P78 and P99) revealed a limited number of variations. The largest one was a deletion of 1363 bp in the predicted ORF150, which was detected in P78, but not in P99. This unexpected finding was confirmed by conventional PCR and digital PCR. The results presented here primarily suggest that, CyHV-3 evolves, at least in vitro, through an assemblage of haplotypes that alternatively become dominant or under-represented. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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11 pages, 1288 KiB  
Communication
Shedding of the Salmonid Herpesvirus-3 by Infected Lake Trout (Salvelinus namaycush)
by Mohamed Faisal, Mochamad Purbayu, Megan A. Shavalier, Terence L. Marsh and Thomas P. Loch
Viruses 2019, 11(7), 580; https://0-doi-org.brum.beds.ac.uk/10.3390/v11070580 - 26 Jun 2019
Cited by 2 | Viewed by 3193
Abstract
Salmonid Herpesvirus-3, commonly known as the Epizootic Epitheliotropic Disease virus (EEDV), causes a disease of lake trout (Salvelinus namaycush) that has killed millions of fish over the past several decades. Currently, most aspects of EEDV disease ecology remain unknown. In this [...] Read more.
Salmonid Herpesvirus-3, commonly known as the Epizootic Epitheliotropic Disease virus (EEDV), causes a disease of lake trout (Salvelinus namaycush) that has killed millions of fish over the past several decades. Currently, most aspects of EEDV disease ecology remain unknown. In this study, we investigated EEDV shedding in experimentally challenged (intracoelomic injection) lake trout that were individually microchipped. In order to assess viral shedding, each infected fish was placed in individual static, aerated aquaria for a period of 8 h, after which the water was assessed for the presence of EEDV DNA using quantitative PCR. Water sampling was conducted every seven days for 93 days post-infection (pi), followed by additional sampling after one year. Results demonstrated that lake trout began shedding EEDV into the water as early as 9 days pi. Shedding peaked approximately three weeks pi and ceased after nine weeks pi. In contrast, mortalities did not occur until 40 days pi. Although mortality reached 73.9%, surviving fish ceased shedding and continued to grow. However, additional shedding was detected 58 weeks after infection in 66% of surviving fish. Findings of this study demonstrate that EEDV is shed into the water by infected lake trout hosts for extended periods of time, a mechanism that favors virus dissemination. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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Review

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42 pages, 3711 KiB  
Review
Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development
by Jakub Treml, Markéta Gazdová, Karel Šmejkal, Miroslava Šudomová, Peter Kubatka and Sherif T. S. Hassan
Viruses 2020, 12(2), 154; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020154 - 29 Jan 2020
Cited by 57 | Viewed by 6678
Abstract
Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance [...] Read more.
Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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18 pages, 2616 KiB  
Review
Herpes Virus, Oral Clinical Signs and QoL: Systematic Review of Recent Data
by Salvatore Crimi, Luca Fiorillo, Alberto Bianchi, Cesare D’Amico, Giulia Amoroso, Francesca Gorassini, Roberta Mastroieni, Stefania Marino, Cristina Scoglio, Francesco Catalano, Paola Campagna, Salvatore Bocchieri, Rosa De Stefano, Maria Teresa Fiorillo and Marco Cicciù
Viruses 2019, 11(5), 463; https://0-doi-org.brum.beds.ac.uk/10.3390/v11050463 - 21 May 2019
Cited by 74 | Viewed by 16492
Abstract
This manuscript aims to highlight all the clinical features of the herpes virus, with a particular focus on oral manifestations and in the maxillofacial district about Herpes Simplex Virus-1 (HSV-1) and Herpes Simplex Virus-2 (HSV-2). Oral herpes virus is a very common and [...] Read more.
This manuscript aims to highlight all the clinical features of the herpes virus, with a particular focus on oral manifestations and in the maxillofacial district about Herpes Simplex Virus-1 (HSV-1) and Herpes Simplex Virus-2 (HSV-2). Oral herpes virus is a very common and often debilitating infectious disease for patients, affecting oral health and having important psychological implications. The collection of relevant data comes from the scientific databases Pubmed, Embase; initially this collection obtained an extremely high number of results, 1415. After applying the inclusion and exclusion criteria, as well as a manual screening, the results included in this review were limited to 14. The results were expressed by evaluating all the signs and symptoms that this pathology entails during the study, paying attention to the characteristics linked to the quality of life and the psychological implications. This pathology has numerous therapies, which often make the healing phase of the manifestations of this viral pathology more comfortable. The therapies currently used for the treatment of this viral infection are pharmacological, topical, systemic, or instrumental, for example with laser devices. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
18 pages, 3332 KiB  
Review
Terminase Large Subunit Provides a New Drug Target for Herpesvirus Treatment
by Linlin Yang, Qiao Yang, Mingshu Wang, Renyong Jia, Shun Chen, Dekang Zhu, Mafeng Liu, Ying Wu, Xinxin Zhao, Shaqiu Zhang, Yunya Liu, Yanling Yu, Ling Zhang, Xiaoyue Chen and Anchun Cheng
Viruses 2019, 11(3), 219; https://0-doi-org.brum.beds.ac.uk/10.3390/v11030219 - 05 Mar 2019
Cited by 14 | Viewed by 5814
Abstract
Herpesvirus infection is an orderly, regulated process. Among these viruses, the encapsidation of viral DNA is a noteworthy link; the entire process requires a powered motor that binds to viral DNA and carries it into the preformed capsid. Studies have shown that this [...] Read more.
Herpesvirus infection is an orderly, regulated process. Among these viruses, the encapsidation of viral DNA is a noteworthy link; the entire process requires a powered motor that binds to viral DNA and carries it into the preformed capsid. Studies have shown that this power motor is a complex composed of a large subunit, a small subunit, and a third subunit, which are collectively known as terminase. The terminase large subunit is highly conserved in herpesvirus. It mainly includes two domains: the C-terminal nuclease domain, which cuts the viral concatemeric DNA into a monomeric genome, and the N-terminal ATPase domain, which hydrolyzes ATP to provide energy for the genome cutting and transfer activities. Because this process is not present in eukaryotic cells, it provides a reliable theoretical basis for the development of safe and effective anti-herpesvirus drugs. This article reviews the genetic characteristics, protein structure, and function of the herpesvirus terminase large subunit, as well as the antiviral drugs that target the terminase large subunit. We hope to provide a theoretical basis for the prevention and treatment of herpesvirus. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
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