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9 pages, 1205 KiB

Open AccessArticle

Effect of Lactococcus lactis Strain Plasma on HHV-6 and HHV-7 Shedding in Saliva: A Prospective Observational Study

by Hiroki Miura, Masaru Ihira, Kei Kozawa, Yoshiki Kawamura, Yuki Higashimoto, Fumihiko Hattori and Tetsushi Yoshikawa

Microorganisms 2021, 9(8), 1683; https://doi.org/10.3390/microorganisms9081683 - 8 Aug 2021

Cited by 1 | Viewed by 2723

Abstract

HHV-6 and HHV-7 can reactivate in the salivary gland in response to various host stresses. Lactococcus lactis strain Plasma (LC-Plasma) can activate plasmacytoid dendritic cells (pDCs) and decrease viral infection. We investigated whether LC-Plasma intake could decrease HHV-6 and HHV-7 reactivation in the [...] Read more.

HHV-6 and HHV-7 can reactivate in the salivary gland in response to various host stresses. Lactococcus lactis strain Plasma (LC-Plasma) can activate plasmacytoid dendritic cells (pDCs) and decrease viral infection. We investigated whether LC-Plasma intake could decrease HHV-6 and HHV-7 reactivation in the salivary gland. A total of 54 healthy volunteers were enrolled in this study. Participants took LC-Plasma granules daily for 6 weeks. Saliva samples were collected from subjects weekly for 4 weeks before (first), during (second), and after (third period) LC-Plasma intake. There was a 2-week interval between the first and second periods and a 3-week interval between the second and third periods. Mean salivary HHV-6 and HHV-7 DNA loads were compared among the three observation periods. In the first period (baseline data of viral DNA shedding), HHV-6 DNA shedding was significantly higher in subjects under 40 years old, and HHV-7 DNA shedding was significantly higher in males. HHV-6 and HHV-7 DNA loads did not significantly differ between periods. Meanwhile, in a subgroup analysis of the subjects under 40 years old, HHV-6 DNA load was significantly lower in the second period than in the first period. LC-Plasma decreases HHV-6 reactivation in the salivary glands in younger adults. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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16 pages, 2849 KiB

Open AccessArticle

Kaposi’s Sarcoma-Associated Herpesvirus ORF7 Is Essential for Virus Production

by Yuki Iwaisako, Tadashi Watanabe, Mizuki Hanajiri, Yuichi Sekine and Masahiro Fujimuro

Microorganisms 2021, 9(6), 1169; https://doi.org/10.3390/microorganisms9061169 - 28 May 2021

Cited by 5 | Viewed by 3065

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman disease. Although capsid formation and maturation in the alpha-herpesvirus herpes simplex virus 1 are well understood, these processes in KSHV remain unknown. The KSHV ORF7, encoding the viral terminase [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman disease. Although capsid formation and maturation in the alpha-herpesvirus herpes simplex virus 1 are well understood, these processes in KSHV remain unknown. The KSHV ORF7, encoding the viral terminase (DNA cleavage and packaging protein), is thought to contribute to capsid formation; however, functional information is lacking. Here, we investigated the role of ORF7 during KSHV lytic replication by generating two types of ORF7 knock-out (KO) mutants (frameshift-induced and stop codon-induced ORF7 deficiency), KSHV BAC16, and its revertants. The results revealed that both ORF7-KO KSHVs showed significantly reduced viral production but there was no effect on lytic gene expression and viral genome replication. Complementation assays showed virus production from cells harboring ORF7-KO KSHV could be recovered by ORF7 overexpression. Additionally, exogenously expressed ORF7 partially induced nuclear relocalization of the other terminase components, ORF29 and ORF67.5. ORF7 interacted with both ORF29 and ORF67.5, whereas ORF29 and ORF67.5 failed to interact with each other, suggesting that ORF7 functions as a hub molecule in the KSHV terminase complex for interactions between ORF29 and ORF67.5. These findings indicate that ORF7 plays a key role in viral replication, as a component of terminase. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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19 pages, 13136 KiB

Open AccessArticle

Live-Cell Analysis of Human Cytomegalovirus DNA Polymerase Holoenzyme Assembly by Resonance Energy Transfer Methods

by Veronica Di Antonio, Giorgio Palù and Gualtiero Alvisi

Microorganisms 2021, 9(5), 928; https://doi.org/10.3390/microorganisms9050928 - 26 Apr 2021

Cited by 4 | Viewed by 3074

Abstract

Human cytomegalovirus (HCMV) genome replication is a complex and still not completely understood process mediated by the highly coordinated interaction of host and viral products. Among the latter, six different proteins form the viral replication complex: a single-stranded DNA binding protein, a trimeric [...] Read more.

Human cytomegalovirus (HCMV) genome replication is a complex and still not completely understood process mediated by the highly coordinated interaction of host and viral products. Among the latter, six different proteins form the viral replication complex: a single-stranded DNA binding protein, a trimeric primase/helicase complex and a two subunit DNA polymerase holoenzyme, which in turn contains a catalytic subunit, pUL54, and a dimeric processivity factor ppUL44. Being absolutely required for viral replication and representing potential therapeutic targets, both the ppUL44–pUL54 interaction and ppUL44 homodimerization have been largely characterized from structural, functional and biochemical points of view. We applied fluorescence and bioluminescence resonance energy transfer (FRET and BRET) assays to investigate such processes in living cells. Both interactions occur with similar affinities and can take place both in the nucleus and in the cytoplasm. Importantly, single amino acid substitutions in different ppUL44 domains selectively affect its dimerization or ability to interact with pUL54. Intriguingly, substitutions preventing DNA binding of ppUL44 influence the BRET_max of protein–protein interactions, implying that binding to dsDNA induces conformational changes both in the ppUL44 homodimer and in the DNA polymerase holoenzyme. We also compared transiently and stably ppUL44-expressing cells in BRET inhibition assays. Transient expression of the BRET donor allowed inhibition of both ppUL44 dimerization and formation of the DNA polymerase holoenzyme, upon overexpression of FLAG-tagged ppUL44 as a competitor. Our approach could be useful both to monitor the dynamics of assembly of the HCMV DNA polymerase holoenzyme and for antiviral drug discovery. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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10 pages, 1253 KiB

Open AccessArticle

Hippocampal Atrophy in Pediatric Transplant Recipients with Human Herpesvirus 6B

by Misa Miyake, Yoshiki Kawamura, Naoko Ishihara, Shigetaka Suzuki, Hiroki Miura, Yoko Sakaguchi, Masaharu Tanaka, Yoshiyuki Takahashi, Seiji Kojima, Hiroshi Toyama, Jun Natsume and Tetsushi Yoshikawa

Microorganisms 2021, 9(4), 776; https://doi.org/10.3390/microorganisms9040776 - 8 Apr 2021

Viewed by 2143

Abstract

The aim of this study was to determine whether human herpesvirus 6B (HHV-6B) infection can impair the hippocampus in pediatric hematopoietic stem cell transplant (HSCT) recipients. Study subjects were pediatric HSCT recipients monitored for HHV-6B infection who underwent brain MRI before and after [...] Read more.

The aim of this study was to determine whether human herpesvirus 6B (HHV-6B) infection can impair the hippocampus in pediatric hematopoietic stem cell transplant (HSCT) recipients. Study subjects were pediatric HSCT recipients monitored for HHV-6B infection who underwent brain MRI before and after transplantation. Volumetric analysis of the hippocampus was performed. Of the 107 patients that received HSCT at Nagoya University Hospital Between July 2008 and April 2014, 20 were eligible for volumetric analysis. Eight patients had HHV-6B infection, of whom two had encephalopathy at the time of HHV-6B infection. None of the 12 patients without HHV-6B infection had encephalopathy. The median ratio of the right hippocampal volume from before to after transplantation was 0.93 in patients with HHV-6B infection and 1.02 in without HHV-6B infection (p = 0.007). The median ratio of the left hippocampal volume ratio in patients with and without HHV-6B infection was 0.92 and 1.00, respectively (p = 0.003). Among the eight patients with HHV-6B infection, four had a marked reduction in hippocampal volume (volume ratio < 0.90). Only one of these patients had neurological symptoms at the time of HHV-6B infection. The reduction in the hippocampal volume ratio was higher in pediatric HSCT recipients with HHV-6B infection than those without viral infection. Neurological follow-up may be required for pediatric HSCT recipients with HHV-6B infection. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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Review

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13 pages, 2849 KiB

Open AccessReview

Functionalized Noble Metal Nanoparticles for the Treatment of Herpesvirus Infection

by Martyna Janicka, Katarzyna Ranoszek-Soliwoda, Grzegorz Chodaczek, Małgorzata Antos-Bielska, Marek Brytan, Emilia Tomaszewska, Grzegorz Celichowski, Jarosław Grobelny, Joanna Cymerys, Małgorzata Krzyżowska and Marcin Chodkowski

Microorganisms 2022, 10(11), 2161; https://doi.org/10.3390/microorganisms10112161 - 31 Oct 2022

Cited by 2 | Viewed by 1515

Abstract

Neuroinfections caused by herpesviruses, mainly by HHV-1, represent a significant problem for modern medicine due to the small number of therapeutic substances available in the pharmaceutical sector. Furthermore, HHV-1 infection has been linked to neurodegenerative processes such as Alzheimer’s disease, which justifies the [...] Read more.

Neuroinfections caused by herpesviruses, mainly by HHV-1, represent a significant problem for modern medicine due to the small number of therapeutic substances available in the pharmaceutical sector. Furthermore, HHV-1 infection has been linked to neurodegenerative processes such as Alzheimer’s disease, which justifies the search for new effective therapies. The development of nanotechnology opens up new possibilities for the treatment of neuroinflammation. Gold and silver nanoparticles are gaining popularity, and the number of clinical trials involving metallic nanoparticles is constantly increasing. This paper reviews the research on gold and silver nanoparticles and their potential use in the treatment of herpesvirus neuroinfection. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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21 pages, 1209 KiB

Open AccessReview

Role of Epitranscriptomic and Epigenetic Modifications during the Lytic and Latent Phases of Herpesvirus Infections

by Abel A. Soto, Gerardo Ortiz, Sofía Contreras, Ricardo Soto-Rifo and Pablo A. González

Microorganisms 2022, 10(9), 1754; https://doi.org/10.3390/microorganisms10091754 - 30 Aug 2022

Cited by 4 | Viewed by 2496

Abstract

Herpesviruses are double-stranded DNA viruses occurring at a high prevalence in the human population and are responsible for a wide array of clinical manifestations and diseases, from mild to severe. These viruses are classified in three subfamilies (Alpha-, Beta- and Gammaherpesvirinae [...] Read more.

Herpesviruses are double-stranded DNA viruses occurring at a high prevalence in the human population and are responsible for a wide array of clinical manifestations and diseases, from mild to severe. These viruses are classified in three subfamilies (Alpha-, Beta- and Gammaherpesvirinae), with eight members currently known to infect humans. Importantly, all herpesviruses can establish lifelong latent infections with symptomatic or asymptomatic lytic reactivations. Accumulating evidence suggest that chemical modifications of viral RNA and DNA during the lytic and latent phases of the infections caused by these viruses, are likely to play relevant roles in key aspects of the life cycle of these viruses by modulating and regulating their replication, establishment of latency and evasion of the host antiviral response. Here, we review and discuss current evidence regarding epitranscriptomic and epigenetic modifications of herpesviruses and how these can influence their life cycles. While epitranscriptomic modifications such as m⁶A are the most studied to date and relate to positive effects over the replication of herpesviruses, epigenetic modifications of the viral genome are generally associated with defense mechanisms of the host cells to suppress viral gene transcription. However, herpesviruses can modulate these modifications to their own benefit to persist in the host, undergo latency and sporadically reactivate. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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14 pages, 1591 KiB

Open AccessReview

Replication Compartments—The Great Survival Strategy for Epstein–Barr Virus Lytic Replication

by Atsuko Sugimoto

Microorganisms 2022, 10(5), 896; https://doi.org/10.3390/microorganisms10050896 - 25 Apr 2022

Cited by 3 | Viewed by 2875

Abstract

During Epstein–Barr virus (EBV) lytic replication, viral DNA synthesis is carried out in viral replication factories called replication compartments (RCs), which are located at discrete sites in the nucleus. Viral proteins constituting the viral replication machinery are accumulated in the RCs to amplify [...] Read more.

During Epstein–Barr virus (EBV) lytic replication, viral DNA synthesis is carried out in viral replication factories called replication compartments (RCs), which are located at discrete sites in the nucleus. Viral proteins constituting the viral replication machinery are accumulated in the RCs to amplify viral genomes. Newly synthesized viral DNA is stored in a subdomain of the RC termed the BMRF1-core, matured by host factors, and finally packed into assembled viral capsids. Late (L) genes are transcribed from DNA stored in the BMRF1-core through a process that is mainly dependent on the viral pre-initiation complex (vPIC). RC formation is a well-regulated system and strongly advantageous for EBV survival because of the following aspects: (1) RCs enable the spatial separation of newly synthesized viral DNA from the cellular chromosome for protection and maturation of viral DNA; (2) EBV-coded proteins and their interaction partners are recruited to RCs, which enhances the interactions among viral proteins, cellular proteins, and viral DNA; (3) the formation of RCs benefits continuous replication, leading to L gene transcription; and (4) DNA storage and maturation leads to efficient progeny viral production. Here, we review the state of knowledge of this important viral structure and discuss its roles in EBV survival. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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8 pages, 4657 KiB

Open AccessReview

Human Herpesvirus and the Immune Checkpoint PD-1/PD-L1 Pathway: Disorders and Strategies for Survival

by Takayuki Murata

Microorganisms 2021, 9(4), 778; https://doi.org/10.3390/microorganisms9040778 - 8 Apr 2021

Cited by 9 | Viewed by 2644

Abstract

The immune system has evolved as a complex and efficient means of coping with extrinsic materials, such as pathogens and toxins, as well as intrinsic abnormalities, such as cancers. Although rapid and timely activation of the immune system is obviously important, regulated downregulation [...] Read more.

The immune system has evolved as a complex and efficient means of coping with extrinsic materials, such as pathogens and toxins, as well as intrinsic abnormalities, such as cancers. Although rapid and timely activation of the immune system is obviously important, regulated downregulation of the system is almost as significant as activation to prevent runaway immunity, such as allergies and hypercytokinemia. Therefore, the immune checkpoint programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is beneficial for the host. On the other hand, pathogens have evolved to evade host immunity by taking advantage of the PD-1/PD-L1 pathway. This review is focused on human herpesviruses, such as herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV), which cause various types of disorders, and their relationships with the PD-1/PD-L1 pathway. Understanding such relationships will be useful for developing preventative and therapeutic methods for disorders caused by herpesviruses. Full article

(This article belongs to the Special Issue Herpesviruses: Basic, Applicative, and Translational Studies)

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