COVID-19 pandemic as a risk factor for the reactivation of herpes viruses.

The appearance on the skin of herpes virus lesions, concomitantly with the coronavirus disease 2019 (COVID-19) pandemic, leads us to suspect an underlying infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Diagnostic reverse transcriptase polymerase chain reaction tests and immunoglobulin M (IgM) and IgG seroconversion studies have therefore been carried out. We present three cases of herpes virus infections in immunocompetent patients: one of the infections was herpes simplex 1 in a 40-year-old woman, and the other two were herpes varicella-zoster infections in a 62-year-old man and a 25-year-old woman. The patients were in the care of the southern health district of Seville of the SAS (Andalusian Health Service) during the Spanish state of alarm over the COVID-19 pandemic. The SARS-CoV-2 infection was confirmed in only one of the three cases. In this study, we briefly review the etiopathogenic role of the COVID-19 pandemic situation, whereby immunodeficiencies are generated that favour the appearance of other viral infections, such as herpes virus infections.

Bioactive Natural Antivirals: An Updated Review of the Available Plants and Isolated Molecules.

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.

Inhibition of Herpes Simplex Viruses, Types 1 and 2, by Ginsenoside 20(S)-Rg3.

Infections by herpes simplex viruses have an immense impact on humans, ranging from selflimiting, benign illness to serious, life-threatening diseases. While nucleoside analog drugs are available, resistance has been increasing and currently no vaccine exists. Ginsenosides derived from Panax ginseng have been documented to inhibit several viruses and bolster immune defenses. This study evaluated 12 of the most relevant ginsenosides from P. ginseng for toxicities and inhibition of herpes simplex viruses types 1 and 2 in Vero cells. The effects of test compounds and virus infection were determined using a PrestoBlue cell viability assay. Time course studies were also conducted to better understand at what points the virus life cycle was affected. Non-toxic concentrations of the ginsenosides were determined and ranged from 12.5 µM to greater than 100 µM. Ginsenoside 20(S)-Rg3 demonstrated the greatest inhibitory effect and was active against both HSV-1 and HSV-2 with an IC50 of approximately 35 µM. The most dramatic inhibition-over 100% compared to controls-occurred when the virus was exposed to 20(S)-Rg3 for 4 h prior to being added to cells. 20(S)-Rg3 holds promise as a potential chemotherapeutic agent against herpes simplex viruses and, when used together with valacyclovir, may prevent increased resistance to drugs.

Essential Oils for the Treatment of Herpes Simplex Virus Infections.

Infections with herpes simplex virus type (HSV)-1 and HSV-2 are distributed worldwide. Although standard therapies with acyclovir and other synthetic drugs are available, the safety and efficacy of these drugs are limited due to the development of drug resistance and adverse side effects. The literature on essential oils and isolated compounds was reviewed regarding their antiviral activities against HSV-1 and HSV-2. The present overview aims to review experimental data and clinical trials focusing on the antiviral activity of selected essential oils and isolated oil components. HSV was found to be susceptible to many essential oils and their constituents. Whereas some essential oils and compounds exhibit direct virucidal activity or inhibit intracellular replication, many essential oils and compounds interact with HSV particles thereby inhibiting cell adsorption. Ayclovir-resistant HSV strains are also susceptible to essential oils since their mode of action is different from the synthetic drug. There are numerous publications on the antiherpetic activity of essential oils and their isolated active compounds. This field of research is still growing, and more clinical trials are required to explore the full potential of different essential oils for the topical treatment of herpetic infections.

A case of herpes simplex virus reactivation after fractional ablative carbon dioxide laser to treat a burn scar.

Fractional photothermolysis was initially introduced by Manstein in 2004 .Fractional CO2 laser technology introduced has allowed physicians to obtain good cosmetic results with a lower rate of complications than non-fractionated ablative laser treatment. However, adverse effects may still occur.Reported cases of HSV infection after fractional photothermolysis are rare. A 48-year-old woman with Fitzpatrick skin type III presented with a scar in her perioral area desiring esthetic improvement of her burn scar. She didn't have a history of recurrent herpes simplex virus (HSV) infection periorally. A fractionated resurfacing laser Quadralase (Candela) was used to treat her perioral burn scar. Two sessions were performed with a month interval. Five days after the second session of laser therapy even after she took antiviral prophylaxis based on valacyclovir 500mg twice daily 24 hours before the laser session and 3 days after, she presented with a rash on the perioral area preceded by pain. Correlation of the history and the clinical presentation was consistent with HSV reactivation. Treatment was initiated with acyclovir 10mg/kg/8h administered intravenously for 10 days with a clearing of her vesicular eruption. Fractional CO2 laser is a very safe procedure when used with accepted parameters. Early recognition, close monitoring and careful wound care will prevent long term sequelae when complications occur.

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

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-1ß and TNF-α.

Interferon epsilon in the reproductive tract of healthy and genital herpes simplex virus-infected pregnant women: Results of a pilot study.

PROBLEM: Recently characterized interferon epsilon (IFNe) protects against sexually transmitted infections, including genital herpes simplex virus (HSV), in animal models. There are no reports of IFNe in genital tract secretions of pregnant women, and data on IFNe in non-pregnant women are limited. This pilot study is the first to measure concentrations of IFNe in vaginal and cervical secretions during pregnancy and compare values between healthy and genital HSV-infected women. METHOD OF STUDY: Vaginal or cervical specimens from 30 pregnant women were obtained from the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) repository. Cervical samples were collected during the first trimester and vaginal samples across pregnancy. Enzyme-linked immunosorbent assay determined concentrations of IFNe (pg/mL). Data for IFNe were log-transformed and compared by maternal demographics, clinical variables, and HSV status using t tests and linear regression. Repeated measures analysis explored trends across pregnancy. RESULTS: Among the entire cohort, first trimester concentrations of IFNe in vaginal or cervical secretions decreased as body mass index increased (ß = -0.14, P = .0466). Concentrations of vaginal IFNe increased across pregnancy in HSV-infected and healthy women (P = .009). Average vaginal IFNe across pregnancy was lower in women with HSV compared to healthy women (P = .0009). CONCLUSION: Interferon epsilon increased across pregnancy, but was less abundant in women with HSV. This pilot investigation cannot make any definitive conclusions. However, animal models suggest that IFNe may protect against STIs. Thus, larger studies are required to validate expression of IFNe in the reproductive tract of pregnant women with and without genital infections.

Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection.

BACKGROUND/AIMS: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-ß) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. METHODS: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells. RESULTS: YY1 was shown to interact with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression levels were decreased. YY1 knockdown led to a considerable downregulation of phosphorylated (p) TBK1 and pIRF3 expressions, while YY1 overexpression significantly upregulated pTBK1 and pIRF3 expression levels and promoted virus-induced IFN-ß production. Additionally, YY1 knockdown led to a significant upregulation of pSTAT1, pSTAT2 and antiviral interferon-stimulated genes, and inhibited viral replication. CONCLUSION: We demonstrated here that YY1 interacts with STAT1 and dynamically regulates the induction of IFN-1 production and activation of IFN-1 signaling in different stages during viral infection.

Antiviral and Antitumor Activity of Licorice Root Extracts.

BACKGROUND: In the search for anti-viral and antitumor substances from natural resources, antiviral and antitumor activities of licorice root extract and purified ingredients were investigated. MATERIALS AND METHODS: Viability of cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Antiviral activity was quantified by the selectivity index, defined as the ratio of the 50% cytotoxic concentration (CC50) to the 50% effective concentration against human immunodeficiency virus (HIV) or herpes simplex virus (HSV)-infected cells (EC50). The tumor specificity was calculated by the ratio of CC50 against human normal oral cells to that against human oral squamous cell carcinoma cell lines. Licorice flavonoids and lower molecular polyphenols were subjected to quantitative structure-activity relationship analysis. RESULTS: Alkaline extract of licorice root had higher anti-HIV activity than did water extracts, confirming our previous reports. On the other hand, water extract, especially the flavonoid-rich fraction, had higher anti-HSV activity than did the alkaline extract. The flavonoid-rich fraction was more cytotoxic against human oral squamous cell carcinoma cell lines compared to normal oral cells, suggesting their tumor-specific cytotoxicity. CONCLUSION: The present study suggests that water and alkaline extracts of licorice root exert different mechanisms of actions against these two viruses. Physicochemical properties, rather than the category of compounds, may be important in determining their anti-HSV activity.

Interferon-mediated antiviral activities of Angelica tenuissima Nakai and its active components.

Angelica tenuissima Nakai is a widely used commodity in traditional medicine. Nevertheless, no study has been conducted on the antiviral and immune-modulatory properties of an aqueous extract of Angelica tenuissima Nakai. In the present study, we evaluated the antiviral activities and the mechanism of action of an aqueous extract of Angelica tenuissima Nakai both in vitro and in vivo. In vitro, an effective dose of Angelica tenuissima Nakai markedly inhibited the replication of Influenza A virus (PR8), Vesicular stomatitis virus (VSV), Herpes simplex virus (HSV), Coxsackie virus, and Enterovirus (EV-71) on epithelial (HEK293T/HeLa) and immune (RAW264.7) cells. Such inhibition can be described by the induction of the antiviral state in cells by antiviral, IFNrelated gene induction and secretion of IFNs and pro-inflammatory cytokines. In vivo, Angelica tenuissima Nakai treated BALB/c mice displayed higher survivability and lower lung viral titers when challenged with lethal doses of highly pathogenic influenza A subtypes (H1N1, H5N2, H7N3, and H9N2). We also found that Angelica tenuissima Nakai can induce the secretion of IL-6, IFN-λ, and local IgA in bronchoalveolar lavage fluid (BALF) of Angelica tenuissima Nakai treated mice, which correlating with the observed prophylactic effects. In HPLC analysis, we found the presence of several compounds in the aqueous fraction and among them; we evaluated antiviral properties of ferulic acid. Therefore, an extract of Angelica tenuissima Nakai and its components, including ferulic acid, play roles as immunomodulators and may be potential candidates for novel anti-viral/anti-influenza agents.

Epimedium koreanum Nakai displays broad spectrum of antiviral activity in vitro and in vivo by inducing cellular antiviral state.

Epimedium koreanum Nakai has been extensively used in traditional Korean and Chinese medicine to treat a variety of diseases. Despite the plant's known immune modulatory potential and chemical make-up, scientific information on its antiviral properties and mode of action have not been completely investigated. In this study, the broad antiviral spectrum and mode of action of an aqueous extract from Epimedium koreanum Nakai was evaluated in vitro, and moreover, the protective effect against divergent influenza A subtypes was determined in BALB/c mice. An effective dose of Epimedium koreanum Nakai markedly reduced the replication of Influenza A Virus (PR8), Vesicular Stomatitis Virus (VSV), Herpes Simplex Virus (HSV) and Newcastle Disease Virus (NDV) in RAW264.7 and HEK293T cells. Mechanically, we found that an aqueous extract from Epimedium koreanum Nakai induced the secretion of type I IFN and pro-inflammatory cytokines and the subsequent stimulation of the antiviral state in cells. Among various components present in the extract, quercetin was confirmed to have striking antiviral properties. The oral administration of Epimedium koreanum Nakai exhibited preventive effects on BALB/c mice against lethal doses of highly pathogenic influenza A subtypes (H1N1, H5N2, H7N3 and H9N2). Therefore, an extract of Epimedium koreanum Nakai and its components play roles as immunomodulators in the innate immune response, and may be potential candidates for prophylactic or therapeutic treatments against diverse viruses in animal and humans.

Aqueous extract from a Chaga medicinal mushroom, Inonotus obliquus (higher Basidiomycetes), prevents herpes simplex virus entry through inhibition of viral-induced membrane fusion.

Chaga medicinal mushroom, Inonotus obliquus, a popular prescription in traditional medicine in Europe and Asia, was used to reduce inflammation in the nasopharynx and to facilitate breathing. The aqueous extract from I. obliquus (AEIO) exhibited marked decrease in herpes simplex virus (HSV) infection (the 50% inhibitory concentration was 3.82 µg/mL in the plaque reduction assay and 12.29 µg/mL in the HSV-1/blue assay) as well as safety in Vero cells (the 50% cellular cytotoxicity was > 1 mg/mL, and selection index was > 80). Using a time course assay, effective stage analysis, and fusion inhibition assay, the mechanism of anti-HSV activity was found against the early stage of viral infection through inhibition of viral-induced membrane fusion. Therefore, AEIO could effectively prevent HSV-1 entry by acting on viral glycoproteins, leading to the prevention of membrane fusion, which is different from nucleoside analog antiherpetics.

Fusogenic oncolytic herpes simplex viruses as a potent and personalized cancer vaccine.

The recent FDA approval of Sipuleucel-T for the treatment of prostate cancer represents an important milestone of cancer immunotherapy, which, for the first time, validates the concept of bringing true clinical benefit to cancer patients by stimulating patients' own anti-tumor immunity. Among the different experimental cancer immunotherapies, oncolytic virotherapy may represent a low-cost yet potent and personalized cancer vaccine for the treatment of solid tumors. This review describes the constructions of several human herpes simplex virus (HSV)-derived oncolytic viruses as candidate cancer vaccines, which induce specific and potent anti-tumor immunity in pre-clinical models, and thus resulting in stronger overall anti-tumor efficacy as compared to oncolytic effect alone. This article also describes the approaches to enhance the antitumor immunity of oncolytic HSVs, and in particular, the key role played by integrating membrane-fusion activity into these viruses. Additionally, this article reviews the potential effect of certain chemotherapeutic agents (e.g. cyclophosphamide) in boosting antitumor immunity induced by oncolytic HSV, and the mechanisms behind it. In summary, all the preclinical and clinical data have suggested that HSV-based oncolytic virotherapies could likely be developed as a new generation of cancer vaccines for the treatment of solid tumors.

The molecular basis of herpesviruses as oncolytic agents.

Herpes simplex viruses (HSVs) have entered clinical trials as oncolytic agents. The following properties make them good candidates. It is a mild pathogen; drugs (Aciclovir) are available to control viral infection; the large genome is amenable to genetic engineering, they can be rendered cancer-specific by deletion of genes, envelope glycoproteins allow the insertion of heterologous ligands to achieve modification of the natural tropism. Genetically modified HSVs have been thoroughly tested in humans. New generation recombinants retargeted to cancer-specific heterologous receptors have been generated and are presently evaluated in pre-clinical settings. They will be reviewed along with the molecular bases of cancer specificity and the strategies for the enhancement of oncolytic potential of HSV recombinants.

Study of antiviral and virucidal activities of aqueous extract of Baccharis articulata against Herpes suis virus.

Baccharis articulata is native of América and traditionally used for the treatment of digestive disorders and urinary infections. Cytotoxicity of aqueous extracts of B. articulata was investigated in Vero cells. As the maximal non cytotoxic concentration has been established, this concentration has been used to evaluate antiviral and virucidal activities against Herpes suis virus type 1, member of the same subfamily of Herpes simplex virus. Aqueous extracts of B. articulata exhibited more than 95% of virucidal activity. These findings support their potential application as a disinfectant or antiseptic with low toxicity and provide a valuable knowledge to ethnopharmacology properties of Baccharis articulata.

Medical application of herpes simplex virus.

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are important human pathogens that cause a variety of diseases from mild skin diseases such as herpes labialis and herpes genitalis to life-threatening diseases such as herpes encephalitis and neonatal herpes. A number of studies have elucidated the roles of this virus in viral replication and pathogenicity, the regulation of gene expression, interaction with the host cell and immune evasion from the host system. This research has allowed the development of potential therapeutic agents and vectors for human diseases. This review focuses on the basic functions and roles of HSV gene products and reviews the current knowledge of medical applications of genetically engineered HSV mutants using different strategies. These major HSV-derived vectors include: (i) amplicons for gene delivery vectors; (ii) replication-defective HSV recombinants for vaccine vectors; (iii) replication-attenuated HSV recombinants for oncolytic virotherapy.

Herpes simplex virus NV1020 as a novel and promising therapy for hepatic malignancy.

BACKGROUND: Patients with hepatic malignancy have a dismal prognosis with standard therapies. NV1020 is an oncolytic herpes simplex virus that has potential to be a safe and effective therapeutic agent for this disease. OBJECTIVE: We set out to discuss the development of NV1020 as an oncolytic agent and explore the potential role of this particular virus in the setting of human hepatic cancer. METHODS: The scope of this review includes an overview of preclinical experience with NV1020, as well as an examination of current standard and developing therapies for liver cancer. The primary focus, however, is on the safety and potential clinical efficacy of NV1020 against hepatic malignancy. RESULTS/CONCLUSION: We have found that NV1020 is a safe, novel therapeutic agent for treatment of refractory hepatic malignancy.

Absence of rapid selection for acyclovir or penciclovir resistance following suboptimal oral prodrug therapy of HSV-infected mice.

BACKGROUND: Acyclovir (ACV) resistant herpes simplex virus (HSV) isolates can be readily selected in animal infection models receiving suboptimal ACV treatment, however no comparative studies of the emergence of resistance following suboptimal treatment with valacyclovir (VCV) or famciclovir (FCV), the prodrugs of acyclovir and penciclovir, respectively, have been reported. METHODS: Mice (n = 30) were infected with HSV type 1 or 2 in the ear pinnae and administered oral prodrugs at one fifth a dose previously shown to be effective. To select and amplify drug-resistant HSV, a total of seven consecutive in vivo passages with suboptimal treatment were performed for each virus sample and progeny virus from each passage was characterized by the plaque reduction (PRA) and plating efficiency assays (PEA). RESULTS: No drug-resistant HSV-2 and only a single drug-resistant HSV-1 variant were identified. Virus recovered from the first three sequential passages of this HSV-1 sample was susceptible by PRA, although the proportion of resistant virus recovered gradually increased upon passage. The resistant HSV-1 phenotype was confirmed by PRA after four sequential passages in mice. Unexpectedly, this in vivo-selected drug-resistant HSV-1 failed to yield an infection completely refractory to treatment in subsequent passages. CONCLUSIONS: Sub-optimal therapy of immunocompetent mice with either VCV or FCV did not readily select for HSV-mutants resistant to either ACV or PCV, suggesting that selection of resistance with either prodrug remains difficult using this system. Futhermore, this study suggests that the PEA may represent a useful adjunct to the PRA for monitoring alterations in the proportion of drug-resistant virus even when no change in IC50 is apparent.

[Determination of the antibacterial and antiviral activity of the essential oil from Minthostachys verticillata (Griseb.) Epling]. / Determinación de la actividad antibacteriana y antiviral del aceite esencial de Minthostachys verticillata (Griseb.) Epling.

The in vitro antiviral activity of the essential oil from Minthostachys verticillata was investigated against herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PrV). The viral inhibition was assayed employing viral plaque reduction assay. The antiviral activity of the essential oil specifically affects PrV and HSV-1 multiplication, since it was found that non toxic effects on cells were observed at the concentrations assayed. The therapeutic index values were 10.0 and 9.5 for HSV-1 and PrV, respectively. The antibacterial activity was studied using a diffusion assay and the broth tube dilution method. Gram-positive bacteria were more sensitive to inhibition by plant essential oil than the gram-negative bacteria. The essential oil of M. verticillata was analyzed by gas chromatography (GC) technique. Of the six components identified in the volatile oil, pulegone (44.56%) and menthone (39.51%) were the major constituents. The antimicrobial activity can be explained to some extent by the presence of pulegone. Results suggest that further investigations concerning the isolation of the substance responsible for the antimicrobial activity and an effort to define the mechanisms of action are warranted.