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Recent Advances of Natural Products in HSV Research

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

Deadline for manuscript submissions: closed (31 August 2018) | Viewed by 55505

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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,

Treatment of infectious diseases remains one of the principal research targets for many researchers and healthcare providers worldwide. Herpes simplex virus (HSV) is a member of Herpesviridae, a wide family of enveloped-DNA viruses that cause several clinically-significant syndromes in both adults and neonates. These syndromes are varied and affected by viral entrance, nature of the disease and degree of host immune competence. Herpesviruses are incurable and persist along with the lifetime of the host. Throughout primary infection, the virus enters the nerve cells to generate latency in sensory neurons and lesions at or near point of entry into the host. Reactivation of latent HSV, especially during the deficiency of immunity induces recurrent infection and transmission to new hosts. More than 80% of humans worldwide are infected with HSV-1, and roughly 40% have recurrent infections. Furthermore, infection with HSV-2 was found to be a high-risk factor for potential HIV infection and invasive cervical carcinoma as well. The worldwide disease burden of HSV is substantial, and acyclovir and related nucleoside analogues (viral DNA polymerase inhibitors) as therapies have led to significantly increased treatment efficacy of HSV infections. Although the treatment of HSV infection has greatly advanced using nucleoside analogues therapy, the treatment efficacy has decreased significantly. This is due to the extensive use of nucleoside analogues drugs, which has created drug resistance, associated with other adverse effects as well. Therefore, the search for new sources to develop new antiherpetic agents has gained major priority to overcome the problem. Natural products as potential, new anti-HSV drugs provide several advantages such as reduced side effects, less resistance, low toxicity and various mechanisms of action. The aim of this Special Issue is to shed light on the recent advances in HSV research including preclinical and clinical studies with emphasis on the use of natural products-derived chemicals or crude extracts in the prevention and treatment potential of HSV infection. Analytical methods for the detection of anti-HSV activity are also welcomed.

Dr. Sherif T. S. Hassan
Guest Editor

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Keywords

HSV infection
anti-viral therapeutics
natural products
phytochemicals
host factors
nucleoside analogues
viral DNA polymerase
viral replication
vaccine development
latency

Published Papers (9 papers)

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Research

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13 pages, 1140 KiB

Open AccessCommunication

Comparison of Anti-Viral Activity of Frog Skin Anti-Microbial Peptides Temporin-Sha and [K³]SHa to LL-37 and Temporin-Tb against Herpes Simplex Virus Type 1

by Maëva Roy, Lucie Lebeau, Céline Chessa, Alexia Damour, Ali Ladram, Bruno Oury, David Boutolleau, Charles Bodet and Nicolas Lévêque

Viruses 2019, 11(1), 77; https://doi.org/10.3390/v11010077 - 18 Jan 2019

Cited by 30 | Viewed by 4691

Abstract

Temporins are anti-microbial peptides synthesized in the skin of frogs of the Ranidae family. The few studies to date that have examined their anti-viral properties have shown that they have potential as anti-viral therapies. In this work, we evaluated the anti-herpes simplex virus type 1 (HSV-1) activity of the temporin-SHa (SHa) and its synthetic analog [K³]SHa. Human cathelicidin LL-37 and temporin-Tb (Tb), previously demonstrated to have anti-HSV-1 properties, were used as positive controls. We observed that SHa and [K³]SHa significantly inhibit HSV-1 replication in human primary keratinocytes when used at micromolar concentrations. This anti-viral activity was equivalent to that of Tb, but lower than that of LL-37. Transcriptomic analyses revealed that SHa did not act through the modulation of the cell innate immune response, but rather, displayed virucidal properties by reducing infectious titer of HSV-1 in suspension. In contrast, pre-incubation of the virus with LL-37 suggests that this peptide does not act directly on the viral particle at non-cytotoxic concentrations tested. The anti-HSV-1 activity of LL-37 appears to be due to the potentiation of cellular anti-viral defenses through the induction of interferon stimulated gene expression in infected primary keratinocytes. This study demonstrated that SHa and [K³]SHa, in addition to their previously reported antibacterial and antiparasitic activities, are direct-acting anti-HSV-1 peptides. Importantly, this study extends the little studied anti-viral attributes of frog temporins and offers perspectives for the development of new anti-HSV-1 therapies. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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18 pages, 2939 KiB

Open AccessArticle

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

by Hui-Jun Dong, Zhao-Hua Wang, Wen Meng, Cui-Cui Li, Yan-Xin Hu, Lei Zhou and Xiao-Jia Wang

Viruses 2018, 10(11), 601; https://doi.org/10.3390/v10110601 - 01 Nov 2018

Cited by 60 | Viewed by 6433

Abstract

To complement traditional antivirals, natural compounds that act via host targets and present high barriers to resistance are of increasing interest. In the work reported here, we detected that homoharringtonine (HHT) presents effective antiviral activity. HHT completely inhibited infections of vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and porcine epidemic diarrhea virus (PEDV) at concentrations of 50, 100, and 500 nM in cell cultures, respectively. Treatment with HHT at doses of 0.05 or 0.2 mg/kg significantly reduced viral load and relieved severe symptoms in PEDV- or NDV-infected animals. HHT treatment, however, moderately inhibited avian influenza virus (AIV) infection, suggesting its potent antiviral action is restricted to a number of classes of RNA viruses. In this study, we also observed that HHT actively inhibited herpes simplex virus type 1 (HSV-1) replication with a 50% inhibitory concentration (IC₅₀) of 139 nM; the treatment with HHT at 1000 nM led to reductions of three orders of magnitude. Moreover, HHT antagonized the phosphorylation level of endogenous and exogenous eukaryotic initiation factor 4E (p-eIF4E), which might regulate the selective translation of specific messenger RNA (mRNA). HHT provides a starting point for further progress toward the clinical development of broad-spectrum antivirals. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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18 pages, 2003 KiB

Open AccessArticle

Herbal Gel Formulation Developed for Anti-Human Immunodeficiency Virus (HIV)-1 Activity Also Inhibits In Vitro HSV-2 Infection

by Nripendra Nath Mishra, Ajay Kesharwani, Aakanksha Agarwal, Suja Kizhiyedath Polachira, Reshmi Nair and Satish Kumar Gupta

Viruses 2018, 10(11), 580; https://doi.org/10.3390/v10110580 - 24 Oct 2018

Cited by 12 | Viewed by 4443

Abstract

Herpes simplex virus-2 (HSV-2) infection is the most common cause of genital ulcers. The impact of ulcers also demonstrates a strong link to the human immunodeficiency virus (HIV) infection. Complications, drug resistance, and side-effects of anti-viral drugs make the treatment of HSV-2 infection challenging. Herbal medicines have shown potential against HSV-2 and HIV infections. In this context, polyherbal gel formulation comprising 50% ethanolic extracts from Acacia catechu, Lagerstroemia speciosa, Terminalia chebula and Phyllanthus emblica has been developed. The gel formulation significantly exhibited virucidal activity against both HIV-1 and HSV-2 infections with IC₅₀, 55.93 ± 5.30 µg/mL and 27.26 ± 4.87 µg/mL, respectively. It also inhibited HSV-2 attachment and penetration to the Vero cells with an IC₅₀ = 46.55 ± 1.25 µg/mL and 54.94 ± 2.52 µg/mL respectively, which were significantly lower than acyclovir. However, acyclovir is more potent in post-infection assay with an IC₅₀ = 0.065 ± 0.01 µg/mL whereas gel formulation showed an IC₅₀ = 469.05 ± 16.65 µg/mL under similar conditions. Gel formulation showed no inhibitory effect on the viability of lactobacilli, human vaginal keratinocyte cells (Vk2/E6E7), and the integrity of the Caco-2 cells monolayer. Gel formulation did not lead to any significant increase in the secretion of pro-inflammatory cytokines and mutagenic index. The proposed gel formulation may be a promising candidate microbicide for the prevention of sexually transmitted HIV-1 and HSV-2. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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17 pages, 2445 KiB

Open AccessArticle

Bowman‒Birk Inhibitor Suppresses Herpes Simplex Virus Type 2 Infection of Human Cervical Epithelial Cells

by Yu Liu, Xi-Qiu Xu, Biao Zhang, Jun Gu, Feng-Zhen Meng, Hang Liu, Li Zhou, Xu Wang, Wei Hou and Wen-Zhe Ho

Viruses 2018, 10(10), 557; https://doi.org/10.3390/v10100557 - 12 Oct 2018

Cited by 6 | Viewed by 4044

Abstract

The Bowman‒Birk inhibitor (BBI), a protease inhibitor derived from soybeans, has been extensively studied in anti-tumor and anti-inflammation research. We recently reported that BBI has an anti-HIV-1 property in primary human macrophages. Because HSV-2 infection plays a role in facilitating HIV-1 sexual transmission, we thus examined whether BBI has the ability to inhibit HSV-2 infection. We demonstrated that BBI could potently inhibit HSV-2 replication in human cervical epithelial cells (End1/E6E7). This BBI-mediated HSV-2 inhibition was partially through blocking HSV-2-mediated activation of NF-κB and p38 MAPK pathways. In addition, BBI could activate the JAK/STAT pathway and enhance the expression of several antiviral interferon-stimulated genes (ISGs). Furthermore, BBI treatment of End1/E6E7 cells upregulated the expression of tight junction proteins and reduced HSV-2-mediated cellular ubiquitinated proteins’ degradation through suppressing the ubiquitin‒proteasome system. These observations indicate that BBI may have therapeutic potential for the prevention and treatment of HSV-2 infections. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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16 pages, 5656 KiB

Open AccessArticle

Photodynamic Inactivation of Herpes Simplex Viruses

by Andrea L.-A. Monjo, Eric S. Pringle, Mackenzie Thornbury, Brett A. Duguay, Susan M. A. Monro, Marc Hetu, Danika Knight, Colin G. Cameron, Sherri A. McFarland and Craig McCormick

Viruses 2018, 10(10), 532; https://doi.org/10.3390/v10100532 - 29 Sep 2018

Cited by 26 | Viewed by 7690

Abstract

Herpes simplex virus (HSV) infections can be treated with direct acting antivirals like acyclovir and foscarnet, but long-term use can lead to drug resistance, which motivates research into broadly-acting antivirals that can provide a greater genetic barrier to resistance. Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species that inactivate microorganisms. The botanical plant extract Orthoquin^TM is a powerful photosensitizer with antimicrobial properties. Here we report that Orthoquin also has antiviral properties. Photoactivated Orthoquin inhibited herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infection of target cells in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. HSV inactivation required direct contact between Orthoquin and the inoculum, whereas pre-treatment of target cells had no effect. Orthoquin did not cause appreciable damage to viral capsids or premature release of viral genomes, as measured by qPCR for the HSV-1 genome. By contrast, immunoblotting for HSV-1 antigens in purified virion preparations suggested that higher doses of Orthoquin had a physical impact on certain HSV-1 proteins that altered protein mobility or antigen detection. Orthoquin PDI also inhibited the non-enveloped adenovirus (AdV) in a dose-dependent manner, whereas Orthoquin-mediated inhibition of the enveloped vesicular stomatitis virus (VSV) was light-independent. Together, these findings suggest that the broad antiviral effects of Orthoquin-mediated PDI may stem from damage to viral attachment proteins. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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15 pages, 2310 KiB

Open AccessArticle

Antiviral Activity of Tannic Acid Modified Silver Nanoparticles: Potential to Activate Immune Response in Herpes Genitalis

by Piotr Orłowski, Andrzej Kowalczyk, Emilia Tomaszewska, Katarzyna Ranoszek-Soliwoda, Agnieszka Węgrzyn, Jakub Grzesiak, Grzegorz Celichowski, Jarosław Grobelny, Kristina Eriksson and Malgorzata Krzyzowska

Viruses 2018, 10(10), 524; https://doi.org/10.3390/v10100524 - 26 Sep 2018

Cited by 93 | Viewed by 7095

Abstract

(1) Background: Tannic acid is a plant-derived polyphenol showing antiviral activity mainly because of an interference with the viral adsorption. In this work, we tested whether the modification of silver nanoparticles with tannic acid (TA-AgNPs) can provide a microbicide with additional adjuvant properties to treat genital herpes infection. (2) Methods: The mouse model of the vaginal herpes simplex virus 2 (HSV-2) infection was used to test immune responses after treatment of the primary infection with TA-AgNPs, and later, after a re-challenge with the virus. (3) Results: The mice treated intravaginally with TA-AgNPs showed better clinical scores and lower virus titers in the vaginal tissues soon after treatment. Following a re-challenge, the vaginal tissues treated with TA-AgNPs showed a significant increase in the percentages of IFN-gamma+ CD8+ T-cells, activated B cells, and plasma cells, while the spleens contained significantly higher percentages of IFN-gamma+ NK cells and effector-memory CD8+ T cells in comparison to NaCl-treated group. TA-AgNPs-treated animals also showed significantly better titers of anti-HSV-2 neutralization antibodies in sera; and (4) Conclusions: Our findings suggest that TA-AgNPs sized 33 nm can be an effective anti-viral microbicide to be applied upon the mucosal tissues with additional adjuvant properties enhancing an anti-HSV-2 immune response following secondary challenge. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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18 pages, 1532 KiB

Open AccessArticle

Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti-Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill.

by Viliam Brezáni, Veronika Leláková, Sherif T. S. Hassan, Kateřina Berchová-Bímová, Pavel Nový, Pavel Klouček, Petr Maršík, Stefano Dall’Acqua, Jan Hošek and Karel Šmejkal

Viruses 2018, 10(7), 360; https://doi.org/10.3390/v10070360 - 06 Jul 2018

Cited by 53 | Viewed by 6685

Abstract

Herpes simplex virus (HSV) causes numerous mild-to-serious human diseases, including mucocutaneous herpes infections and life-threatening herpes encephalitis. Moreover, herpes viral lesions can be complicated by inflammation and secondary bacterial infections. The development of resistance to antiviral drugs along with the undesirable side effects of these drugs are relevant argue for the development of new anti-HSV drugs with diverse mechanisms of action. Eucalyptus extracts have been used for decades to combat various infectious diseases. We isolated and studied 12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. The structures were identified by spectroscopic methods (NMR, HR-MS, IR) and all of them were tested for antiherpetic activity against the replication of antigen types HSV-1 and HSV-2. Tereticornate A (12) (IC₅₀: 0.96 μg/mL; selectivity index CC₅₀/IC₅₀: 218.8) showed the strongest activity in the anti-HSV-1 assay, even greater than acyclovir (IC₅₀: 1.92 μg/mL; selectivity index CC₅₀/IC₅₀: 109.4), a standard antiviral drug. Cypellocarpin C (5) (EC₅₀: 0.73 μg/mL; selectivity index CC₅₀/EC₅₀: 287.7) showed the most potent anti-HSV-2 activity, also more intensive than acyclovir (EC₅₀: 1.75 μg/mL; selectivity index CC₅₀/EC₅₀: 120.0). The antimicrobial activity of the isolated compounds was also evaluated against the bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and the yeast Candida albicans. The anti-inflammatory potential was examined using LPS-stimulated THP-1-XBlue™-MD2-CD14 and THP-1 macrophages and focusing on the influences of the NF-κB/AP-1 activity and the secretion of pro-inflammatory cytokines IL-1β and TNF-α. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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Review

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14 pages, 1249 KiB

Open AccessReview

HSV-Induced Systemic Inflammation as an Animal Model for Behçet’s Disease and Therapeutic Applications

by S. M. Shamsul Islam and Seonghyang Sohn

Viruses 2018, 10(9), 511; https://doi.org/10.3390/v10090511 - 19 Sep 2018

Cited by 13 | Viewed by 5391

Abstract

Behçet’s disease (BD) affects multiple organs. It is mainly characterized by recurrent oral, skin, and genital aphthous ulcers, and eye involvement. Successful management of BD is increasing, although its etiology remains unclear. A number of etiologies have been proposed, including environmental, genetic, viral, and immunological factors. To understand its complex etiology and improve its management, animal models of BD have been used to enable more effective therapeutic applications with increased clinical significance. An herpes simplex virus (HSV) type 1-induced BD mouse model has shown disease characteristics similar to those seen in BD patients. An HSV-induced BD animal model has been used to test various therapeutic modalities. The applied modalities are several materials that are derived from natural products, conventional therapeutics, and possible biologics. In this review, we provided how they regulate inflammation in an HSV-induced BD model. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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10 pages, 1138 KiB

Open AccessReview

Resveratrol as a Novel Anti-Herpes Simplex Virus Nutraceutical Agent: An Overview

by Giuseppe Annunziata, Maria Maisto, Connie Schisano, Roberto Ciampaglia, Viviana Narciso, Gian Carlo Tenore and Ettore Novellino

Viruses 2018, 10(9), 473; https://doi.org/10.3390/v10090473 - 03 Sep 2018

Cited by 68 | Viewed by 7677

Abstract

The herpes simplex virus (HSV) is a common human virus affecting many people worldwide. HSV infections manifest with lesions that occur in different parts of the body, including oral, ocular, nasal, and genital skin and mucosa. In rare cases, HSV infections can be serious and lethal. Several anti-HSV drugs have been developed, but the existence of mutant viruses resistant to these drugs led to the individuation of novel antiviral agents. Plant-derived bioactive compounds, and more specifically polyphenols, have been demonstrated to exert marked anti-HSV activity and, among these, resveratrol (RSV) would be considered a good candidate. The purpose of this manuscript is to review the available literature elucidating the efficacy of RSV against HSV and the main demonstrated mechanisms of action. Full article

(This article belongs to the Special Issue Recent Advances of Natural Products in HSV Research)

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