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Recent Advances in Herpesviruses
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Recent Advances in Herpesviruses

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (20 September 2024) | Viewed by 9136

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,

α-β-γ-Herpesviridae belong to the Herpesviridae family. They share the same structure and cycle properties. Herpesviruses are organized in icosahedral capsids that surround DNA-stranded genomic DNA. Usually, a viral genome is an episomal structure during the non-productive cycle. Herpesviruses, in fact, have two cycle steps: they show a latent phase, without productive virions, and a lytic phase, with the release of mature virions. The lytic phase can be induced by several stimuli in vitro and in vivo. The acute infection persists in in vivo models in oropharyngeal epithelium without a release of productive virions. The lytic state is characterized by the expression of specific genes. The lytic proteins are necessary to organize the viral DNA in concatenameric structures and to form the mature capsids. The nucleocapsids are released from the nucleus to the cytosol compartements by a proposed specific model. The nuclear membrane leafts are necessary to organize the nuclear complex to induce the release and translocate the nuclear capsids into the cytosol. The latent phase is characterized by the expression of viral proteins involved in cellular and viral mechanisms. They regulate cell cycle progression, apoptosis and cellular proliferation.

Many attempts are ongoing to study new therapeutical treatments to the aim to improve the conventional therapy.

Dr. Marisa Granato
Guest Editor

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Published Papers (7 papers)

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Editorial

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6 pages, 656 KiB  
Editorial
Vistas in Signaling Pathways Implicated in HSV-1 Reactivation
by Kostas A. Papavassiliou, Amalia A. Sofianidi, Fotios G. Spiliopoulos, Vassiliki A. Gogou and Athanasios G. Papavassiliou
Int. J. Mol. Sci. 2024, 25(22), 12472; https://doi.org/10.3390/ijms252212472 - 20 Nov 2024
Viewed by 298
Abstract
Ancient Greek physicians, including Hippocrates, documented skin conditions resembling herpes as early as 500 before common era (BCE), but it was not until the 1920s that Lowenstein successfully isolated the herpes virus from human lesions, significantly advancing our understanding of the infection [...] [...] Read more.
Ancient Greek physicians, including Hippocrates, documented skin conditions resembling herpes as early as 500 before common era (BCE), but it was not until the 1920s that Lowenstein successfully isolated the herpes virus from human lesions, significantly advancing our understanding of the infection [...] Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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Research

Jump to: Editorial

13 pages, 2785 KiB  
Article
Targeting Peptidylarginine Deiminase 3 to Efficiently Suppress Herpes Simplex Virus Type 2 Infection
by Selina Pasquero, Francesca Gugliesi, Matteo Biolatti, Camilla Albano, Greta Bajetto, Linda Trifirò, Stefano Raviola, Valentina Dell’Oste and Marco De Andrea
Int. J. Mol. Sci. 2024, 25(16), 8709; https://doi.org/10.3390/ijms25168709 - 9 Aug 2024
Cited by 1 | Viewed by 1109
Abstract
Protein expression is regulated through multiple mechanisms, including post-translational modifications (PTMs), which can alter protein structure, stability, localization, and function. Among these, citrullination stands out due to its ability to convert arginine residues into citrulline, altering protein charge and mass. This modification is [...] Read more.
Protein expression is regulated through multiple mechanisms, including post-translational modifications (PTMs), which can alter protein structure, stability, localization, and function. Among these, citrullination stands out due to its ability to convert arginine residues into citrulline, altering protein charge and mass. This modification is catalyzed by calcium-dependent protein arginine deiminases (PADs), enzymes implicated in various inflammatory diseases. We have recently shown that human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) exploit these enzymes to enhance their replication capabilities. Although the role of PADs in HCMV and HSV-1 infections is well documented, their involvement in HSV-2 infection has not yet been thoroughly investigated. Here, we demonstrate that HSV-2 manipulates the overall protein citrullination profile by activating three PAD isoforms: PAD2, PAD3, and PAD4. However, as previously observed during HSV-1 infection, PAD3 is the most significantly upregulated isoform, both at the mRNA and protein levels. Consistently, we demonstrate that inhibiting PAD3, either through the specific inhibitor CAY10727 or via CRISPR/Cas9-mediated gene silencing, markedly reduces HSV-2 replication and viral protein expression. Lastly, we show that CAY10727 displays an IC50 value of 0.3 μM, which is extremely close to what was previously observed for HSV-1. Overall, our findings highlight the crucial role of PAD3 in the life cycle of HSV-2 and suggest that the targeted inhibition of PAD3 may represent a promising approach for treating HSV-2 infections, especially in cases resistant to existing antiviral therapies. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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21 pages, 4390 KiB  
Article
A Combined Transcriptomic and Proteomic Analysis of Monkeypox Virus A23 Protein on HEK293T Cells
by Yihao Wang, Yihan Li, Mingzhi Li, Keyi Wang, Jiaqi Xiong, Ting Wang, Yu Wang, Yunli Guo, Lingbao Kong and Meifeng Li
Int. J. Mol. Sci. 2024, 25(16), 8678; https://doi.org/10.3390/ijms25168678 - 8 Aug 2024
Viewed by 1384
Abstract
Monkeypox virus (MPXV) is a cross-kingdom pathogen infecting both humans and wildlife, which poses a significant health risk to the public. Although MPXV attracts broad attention, there is a lack of adequate studies to elucidate pathogenic mechanisms associated with viral infections. In this [...] Read more.
Monkeypox virus (MPXV) is a cross-kingdom pathogen infecting both humans and wildlife, which poses a significant health risk to the public. Although MPXV attracts broad attention, there is a lack of adequate studies to elucidate pathogenic mechanisms associated with viral infections. In this study, a high-throughput RNA sequencing (RNA-seq) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach was used to explore the transcriptional and metabolic responses of MPXV A23 protein to HEK293T cells. The protein–protein interactions and signaling pathways were conducted by GO and KEGG analyses. The localization of A23 protein in HEK293T cells was detected by immunofluorescence. A total of 648 differentially expressed genes (DEGs) were identified in cells by RNA-Seq, including 314 upregulated genes and 334 downregulated genes. Additionally, liquid chromatography–tandem mass spectrometry (LC-MS/MS) detected 115 cellular proteins that interact with the A23 proteins. Transcriptomic sequencing analysis revealed that transfection of MPXV A23 protein modulated genes primarily associated with cellular apoptosis and DNA damage repair. Proteomic analysis indicated that this protein primarily interacted with host ribosomal proteins and histones. Following the identification of the nuclear localization sequence RKKR within the A23 protein, a truncated mutant A23ΔRKKR was constructed to investigate the subcellular localization of A23 protein. The wild-type A23 protein exhibits a significantly higher nuclear-to-cytoplasmic ratio, exceeding 1.5, in contrast to the mutant A23ΔRKKR, which has a ratio of approximately 1. Immunofluorescence assays showed that the A23 protein was mainly localized in the nucleus. The integration of transcriptomics and proteomics analysis provides a comprehensive understanding of the interaction between MPXV A23 protein and the host. Our findings highlight the potential role of this enzyme in suppressing host antiviral immune responses and modulating host gene expression. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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17 pages, 3588 KiB  
Article
Lytic and Latent Genetic Diversity of the Epstein–Barr Virus Reveals Raji-Related Variants from Southeastern Brazil Associated with Recombination Markers
by Paula D. Alves, Paulo Rohan, Rocio Hassan and Eliana Abdelhay
Int. J. Mol. Sci. 2024, 25(9), 5002; https://doi.org/10.3390/ijms25095002 - 3 May 2024
Viewed by 1107
Abstract
Epstein–Barr virus (EBV) is a ubiquitous gammaherpesvirus etiologically associated with benign and malignant diseases. Since the pathogenic mechanisms of EBV are not fully understood, understanding EBV genetic diversity is an ongoing goal. Therefore, the present work describes the genetic diversity of the lytic [...] Read more.
Epstein–Barr virus (EBV) is a ubiquitous gammaherpesvirus etiologically associated with benign and malignant diseases. Since the pathogenic mechanisms of EBV are not fully understood, understanding EBV genetic diversity is an ongoing goal. Therefore, the present work describes the genetic diversity of the lytic gene BZLF1 in a sampling of 70 EBV-positive cases from southeastern Brazil. Additionally, together with the genetic regions previously characterized, the aim of the present study was to determine the impact of viral genetic factors that may influence EBV genetic diversity. Accordingly, the phylogenetic analysis of the BZLF1 indicated two main clades with high support, BZ-A and BZ-B (PP > 0.85). Thus, the BZ-A clade was the most diverse clade associated with the main polymorphisms investigated, including the haplotype Type 1 + V3 (p < 0.001). Furthermore, the multigene phylogenetic analysis (MLA) between BZLF1 and the oncogene LMP1 showed specific clusters, revealing haplotypic segregation that previous single-gene phylogenies from both genes failed to demonstrate. Surprisingly, the LMP1 Raji-related variant clusters were shown to be more diverse, associated with BZ-A/B and the Type 2/1 + V3 haplotypes. Finally, due to the high haplotypic diversity of the Raji-related variants, the number of DNA recombination-inducing motifs (DRIMs) was evaluated within the different clusters defined by the MLA. Similarly, the haplotype BZ-A + Raji was shown to harbor a greater number of DRIMs (p < 0.001). These results call attention to the high haplotype diversity of EBV in southeast Brazil and strengthen the hypothesis of the recombinant potential of South American Raji-related variants via the LMP1 oncogene. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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14 pages, 3420 KiB  
Article
Carnosic Acid Inhibits Herpes Simplex Virus Replication by Suppressing Cellular ATP Synthesis
by Georgina Horváth, Edit Molnár, Zoltán Szabó, Gábor Kecskeméti, László Juhász, Szabolcs Péter Tallósy, József Nyári, Anita Bogdanov, Ferenc Somogyvári, Valéria Endrész, Katalin Burián and Dezső P. Virok
Int. J. Mol. Sci. 2024, 25(9), 4983; https://doi.org/10.3390/ijms25094983 - 3 May 2024
Cited by 2 | Viewed by 1208
Abstract
Acquiring resistance against antiviral drugs is a significant problem in antimicrobial therapy. In order to identify novel antiviral compounds, the antiviral activity of eight plants indigenous to the southern region of Hungary against herpes simplex virus-2 (HSV-2) was investigated. The plant extracts and [...] Read more.
Acquiring resistance against antiviral drugs is a significant problem in antimicrobial therapy. In order to identify novel antiviral compounds, the antiviral activity of eight plants indigenous to the southern region of Hungary against herpes simplex virus-2 (HSV-2) was investigated. The plant extracts and the plant compound carnosic acid were tested for their effectiveness on both the extracellular and intracellular forms of HSV-2 on Vero and HeLa cells. HSV-2 replication was measured by a direct quantitative PCR (qPCR). Among the tested plant extracts, Salvia rosmarinus (S. rosmarinus) exhibited a 90.46% reduction in HSV-2 replication at the 0.47 μg/mL concentration. Carnosic acid, a major antimicrobial compound found in rosemary, also demonstrated a significant dose-dependent inhibition of both extracellular and intracellular forms of HSV-2. The 90% inhibitory concentration (IC90) of carnosic acid was between 25 and 6.25 μg/mL. Proteomics and high-resolution respirometry showed that carnosic acid suppressed key ATP synthesis pathways such as glycolysis, citrate cycle, and oxidative phosphorylation. Inhibition of oxidative phosphorylation also suppressed HSV-2 replication up to 39.94-fold. These results indicate that the antiviral action of carnosic acid includes the inhibition of ATP generation by suppressing key energy production pathways. Carnosic acid holds promise as a potential novel antiviral agent against HSV-2. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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14 pages, 9135 KiB  
Article
Epstein–Barr Virus DNA Exacerbates Arthritis in a Mouse Model via Toll-like Receptor 9
by Nour Sherri, Rayan Assaf, Elio R. Bitar, Sabah Znait, Abdul Hamid Borghol, Aya Kassem and Elias A. Rahal
Int. J. Mol. Sci. 2024, 25(9), 4661; https://doi.org/10.3390/ijms25094661 - 25 Apr 2024
Viewed by 1166
Abstract
Epstein–Barr virus (EBV) DNA is known to be shed upon reactivation of latent EBV. Based on our previous findings linking Toll-like receptor-9 (TLR9) to an EBV DNA-driven surge in IL-17A production, we aimed to examine the therapeutic potential of TLR9 inhibition in EBV [...] Read more.
Epstein–Barr virus (EBV) DNA is known to be shed upon reactivation of latent EBV. Based on our previous findings linking Toll-like receptor-9 (TLR9) to an EBV DNA-driven surge in IL-17A production, we aimed to examine the therapeutic potential of TLR9 inhibition in EBV DNA-exacerbated arthritis in a collagen-induced arthritis (CIA) mouse model. C57BL/6J mice were administered either collagen, EBV DNA + collagen, EBV DNA + collagen + TLR9 inhibitor, or only the TLR9 inhibitor. After 70 days, paw thicknesses, clinical scores, and gripping strength were recorded. Moreover, affected joints, footpads, and colons were histologically scored. Furthermore, the number of cells co-expressing IL-17A, IFN-γ, and FOXP3 in joint sections was determined by immunofluorescence assays. Significantly decreased paw thicknesses, clinical scores, and histological scores with a significantly increased gripping strength were observed in the group receiving EBV DNA + collagen + TLR9 inhibitor, compared to those receiving EBV DNA + collagen. Similarly, this group showed decreased IL-17A+ IFN-γ+, IL-17A+ FOXP3+, and IL-17A+ IFN-γ+ FOXP3+ foci counts in joints. We show that inhibiting TLR9 limits the exacerbation of arthritis induced by EBV DNA in a CIA mouse model, suggesting that TLR9 could be a potential therapeutic target for rheumatoid arthritis management in EBV-infected individuals. Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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15 pages, 3506 KiB  
Article
Constitutive Interleukin-7 Cytokine Signaling Enhances the Persistence of Epstein–Barr Virus-Specific T-Cells
by Sandhya Sharma, Tim Sauer, Bilal A. Omer, Thomas Shum, Lisa A. Rollins and Cliona M. Rooney
Int. J. Mol. Sci. 2023, 24(21), 15806; https://doi.org/10.3390/ijms242115806 - 31 Oct 2023
Cited by 2 | Viewed by 1873
Abstract
The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors [...] Read more.
The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein–Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral blood T-cells with overlapping peptide libraries spanning the EBV lymphoma antigens, LMP1, LMP2, and EBNA 1, followed by retroviral vector transduction to express the C7R. The C7R increased STAT5 signaling in EBVSTs and enhanced their expansion over 30 days of culture in the presence or absence of exogenous cytokines. C7R-EBVSTs maintained EBV antigen specificity but were dependent on TCR stimulation for continued expansion. C7R-EBVSTs produced more rapid lymphoma control in a murine xenograft model than unmodified EBVSTs and persisted for longer. The findings have led to a clinical trial, evaluating C7R-EBVSTs for the treatment of refractory or relapsed EBV-positive lymphoma (NCT04664179). Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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