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Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases
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Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 25227

Special Issue Editor

Dr. Marisa Granato

E-Mail Website
Guest Editor
1. Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy
2. Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Telematic University, Via di Val Cannuta 247, Rome, Italy
Interests: virology; herpesvirus and cell hots interaction; herpesviruses associated diseases; viruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are gamma-herpesviruses belonging to the Herpesviridae family. They are enveloped viruses with double-stranded DNA (150 kbp) contained within an icosahedral capsid surrounded by an envelope with several glycoproteins (GPs) necessary for the infection of host cells. EBV infects 95% of the population worldwide and is usually asymptomatic. However, several circumstances induce a microenvironment that is related to the onset of some diseases. EBV is the etiological agent of infectious mononucleosis (IM) and is associated with Burkitt’s lymphoma, nasopharyngeal carcinoma, a subtype of gastric cancer, and lymphoproliferative disorders that often arise in solid organ transplantation patients (PTDLs). Several studies have demonstrated that the lytic state is related to the severity of EBV-associated cancer or autoimmunity diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (AR).

KSHV was detected in Kaposi’s sarcoma patients in the 1990s, and it infects endothelial cells, monocytes, dendritic cells (DCs), and T lymphocytes. This virus expresses proteins that mimic cellular molecules regulating proliferation, apoptosis, and autophagy.

With this Special Issue, we wish to present investigations of both conventional and novel treatments of EBV- and KSHV-associated diseases, considering all adverse effects and with the aim of improving therapy outcomes. This Special Issue welcomes the submission of both original research articles and comprehensive review papers (4000+ words) on this topic.

Dr. Marisa Granato
Guest Editor

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Published Papers (6 papers)

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Research

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20 pages, 2068 KiB  
Communication
Epstein–Barr Virus Infection Is Associated with Elevated Hepcidin Levels
by Ximena Duque, Eugenia Mendoza, Segundo Morán, Mayra C. Suárez-Arriaga, Abigail Morales-Sánchez, José I. Fontes-Lemus, Diana A. Domínguez-Martínez and Ezequiel M. Fuentes-Pananá
Int. J. Mol. Sci. 2023, 24(2), 1630; https://doi.org/10.3390/ijms24021630 - 13 Jan 2023
Cited by 1 | Viewed by 3723
Abstract
EBV and Helicobacter pylori (H. pylori) cause highly prevalent persistent infections as early as in childhood. Both pathogens are associated with gastric carcinogenesis. H. pylori interferes with iron metabolism, enhancing the synthesis of acute-phase proteins hepcidin, C-reactive protein (CRP), and α-1 [...] Read more.
EBV and Helicobacter pylori (H. pylori) cause highly prevalent persistent infections as early as in childhood. Both pathogens are associated with gastric carcinogenesis. H. pylori interferes with iron metabolism, enhancing the synthesis of acute-phase proteins hepcidin, C-reactive protein (CRP), and α-1 glycoprotein (AGP), but we do not know whether EBV does the same. In this study, we correlated the EBV antibody levels and the serum levels of hepcidin, CRP, and AGP in 145 children from boarding schools in Mexico City. We found that children IgG positive to EBV antigens (VCA, EBNA1, and EA) presented hepcidin, AGP, and CRP levels higher than uninfected children. Hepcidin and AGP remained high in children solely infected with EBV, while CRP was only significantly high in coinfected children. We observed positive correlations between hepcidin and EBV IgG antibodies (p < 0.5). Using the TCGA gastric cancer database, we also observed an association between EBV and hepcidin upregulation. The TCGA database also allowed us to analyze the two important pathways controlling hepcidin expression, BMP–SMAD and IL-1β/IL-6. We observed only the IL-1β/IL-6-dependent inflammatory pathway being significantly associated with EBV infection. We showed here for the first time an association between EBV and enhanced levels of hepcidin. Further studies should consider EBV when evaluating iron metabolism and anemia, and whether in the long run this is an important mechanism of undernourishment and EBV gastric carcinogenesis. Full article
(This article belongs to the Special Issue Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases)
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11 pages, 1210 KiB  
Communication
Expression of the Chemokine Receptor CCR1 in Burkitt Lymphoma Cell Lines Is Linked to the CD10-Negative Cell Phenotype and Co-Expression of the EBV Latent Genes EBNA2, LMP1, and LMP2
by Laura Zvejniece, Svetlana Kozireva, Zanna Rudevica, Ainars Leonciks, Barbro Ehlin-Henriksson, Elena Kashuba and Irina Kholodnyuk
Int. J. Mol. Sci. 2022, 23(7), 3434; https://doi.org/10.3390/ijms23073434 - 22 Mar 2022
Cited by 3 | Viewed by 2429
Abstract
Chemokines and their receptors regulate the migration of immune cells and the dissemination of cancer cells. CCR1, CCR2, CCR3, and CCR5 all belong to a single protein homology cluster and respond to the same inflammatory chemokines. We previously reported that CCR1 and CCR2B [...] Read more.
Chemokines and their receptors regulate the migration of immune cells and the dissemination of cancer cells. CCR1, CCR2, CCR3, and CCR5 all belong to a single protein homology cluster and respond to the same inflammatory chemokines. We previously reported that CCR1 and CCR2B are induced upon Epstein-Barr virus (EBV) infection of B cells in vitro. EBV is present in almost all cases of endemic Burkitt lymphoma (BL); however, the contribution of EBV in the pathogenesis of the disease is not fully understood. Here, we analyzed the relation of the expression of CCR1, CCR2, CCR3, and CCR5, the EBV DNA load and expression of EBV latent genes in nine EBV-carrying and four EBV-negative BL cell lines. We revealed that CCR1 is expressed at high mRNA and protein levels in two CD10-negative BL cell lines with co-expression of the EBV latent genes EBNA2, LMP1, and LMP2. Low levels of CCR2 transcripts were found in three BL cell lines. CCR3 and CCR5 transcripts were hardly detectable. Our data suggest that in vivo, CCR1 may be involved in the dissemination of BL cells and in the selection of BL cells with restricted EBV gene expression programs. Full article
(This article belongs to the Special Issue Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases)
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25 pages, 5226 KiB  
Article
Latently KSHV-Infected Cells Promote Further Establishment of Latency upon Superinfection with KSHV
by Chen Gam ze Letova, Inna Kalt, Meir Shamay and Ronit Sarid
Int. J. Mol. Sci. 2021, 22(21), 11994; https://doi.org/10.3390/ijms222111994 - 5 Nov 2021
Cited by 3 | Viewed by 2374
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency. Full article
(This article belongs to the Special Issue Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases)
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Review

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22 pages, 1474 KiB  
Review
Epstein–Barr Virus (EBV) Epithelial Associated Malignancies: Exploring Pathologies and Current Treatments
by Oren Shechter, Daniel G. Sausen, Elisa S. Gallo, Harel Dahari and Ronen Borenstein
Int. J. Mol. Sci. 2022, 23(22), 14389; https://doi.org/10.3390/ijms232214389 - 19 Nov 2022
Cited by 16 | Viewed by 8163
Abstract
Epstein–Barr virus (EBV) is one of eight known herpesviruses with the potential to infect humans. Globally, it is estimated that between 90–95% of the population has been infected with EBV. EBV is an oncogenic virus that has been strongly linked to various epithelial [...] Read more.
Epstein–Barr virus (EBV) is one of eight known herpesviruses with the potential to infect humans. Globally, it is estimated that between 90–95% of the population has been infected with EBV. EBV is an oncogenic virus that has been strongly linked to various epithelial malignancies such as nasopharyngeal and gastric cancer. Recent evidence suggests a link between EBV and breast cancer. Additionally, there are other, rarer cancers with weaker evidence linking them to EBV. In this review, we discuss the currently known epithelial malignancies associated with EBV. Additionally, we discuss and establish which treatments and therapies are most recommended for each cancer associated with EBV. Full article
(This article belongs to the Special Issue Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases)
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26 pages, 1356 KiB  
Review
Virus-Mediated Inhibition of Apoptosis in the Context of EBV-Associated Diseases: Molecular Mechanisms and Therapeutic Perspectives
by Zbigniew Wyżewski, Matylda Barbara Mielcarska, Karolina Paulina Gregorczyk-Zboroch and Anna Myszka
Int. J. Mol. Sci. 2022, 23(13), 7265; https://doi.org/10.3390/ijms23137265 - 30 Jun 2022
Cited by 13 | Viewed by 3351
Abstract
Epstein-Barr virus (EBV), the representative of the Herpesviridae family, is a pathogen extensively distributed in the human population. One of its most characteristic features is the capability to establish latent infection in the host. The infected cells serve as a sanctuary for the [...] Read more.
Epstein-Barr virus (EBV), the representative of the Herpesviridae family, is a pathogen extensively distributed in the human population. One of its most characteristic features is the capability to establish latent infection in the host. The infected cells serve as a sanctuary for the dormant virus, and therefore their desensitization to apoptotic stimuli is part of the viral strategy for long-term survival. For this reason, EBV encodes a set of anti-apoptotic products. They may increase the viability of infected cells and enhance their resistance to chemotherapy, thereby contributing to the development of EBV-associated diseases, including Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), gastric cancer (GC), nasopharyngeal carcinoma (NPC) and several other malignancies. In this paper, we have described the molecular mechanism of anti-apoptotic actions of a set of EBV proteins. Moreover, we have reviewed the pro-survival role of non-coding viral transcripts: EBV-encoded small RNAs (EBERs) and microRNAs (miRNAs), in EBV-carrying malignant cells. The influence of EBV on the expression, activity and/or intracellular distribution of B-cell lymphoma 2 (Bcl-2) protein family members, has been presented. Finally, we have also discussed therapeutic perspectives of targeting viral anti-apoptotic products or their molecular partners. Full article
(This article belongs to the Special Issue Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases)
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20 pages, 2914 KiB  
Review
Nanotechnology Frontiers in γ-Herpesviruses Treatments
by Marisa Granato
Int. J. Mol. Sci. 2021, 22(21), 11407; https://doi.org/10.3390/ijms222111407 - 22 Oct 2021
Cited by 6 | Viewed by 3445
Abstract
Epstein–Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients [...] Read more.
Epstein–Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients (PTDLs). KSHV, an etiologic agent of Kaposi’s sarcoma (KS), displays primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Many therapeutics, such as bortezomib, CHOP cocktail medications, and natural compounds (e.g., quercetin or curcumin), are administrated to patients affected by γ-herpesvirus infections. These drugs induce apoptosis and autophagy, inhibiting the proliferative and cell cycle progression in these malignancies. In the last decade, many studies conducted by scientists and clinicians have indicated that nanotechnology and nanomedicine could improve the outcome of several treatments in γ-herpesvirus-associated diseases. Some drugs are entrapped in nanoparticles (NPs) expressed on the surface area of polyethylene glycol (PEG). These NPs move to specific tissues and exert their properties, releasing therapeutics in the cell target. To treat EBV- and KSHV-associated diseases, many studies have been performed in vivo and in vitro using virus-like particles (VPLs) engineered to maximize antigen and epitope presentations during immune response. NPs are designed to improve therapeutic delivery, avoiding dissolving the drugs in toxic solvents. They reduce the dose-limiting toxicity and reach specific tissue areas. Several attempts are ongoing to synthesize and produce EBV vaccines using nanosystems. Full article
(This article belongs to the Special Issue Herpesviruses and Their Host Cells: EBV- and KSHV-Associated Diseases)
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