Interleukin 1βreceptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1

Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.

Streptococcus pneumoniae and Herpes Simplex Virus-1 Central Nervous System Co-Infection

Co-infections of the central nervous system (CNS) caused by bacterial and viral pathogens are considered to be rare. Herpes simplex virus type-1 (HSV-1) reactivation following Streptococcus pneumoniae infection is well described but most cases are related to oral or cutaneous lesions or in respiratory samples. HSV-1 CNS reactivation after Streptococcus pneumoniae meningitis is a very rare event and may have significant morbidity and mortality. In this case report, we describe a 71-year-old female patient that presented with a history of abdominal pain and confusion/disorientation that had tonic-clonic seizures while in the Emergency Department. The diagnostic work-up confirmed CNS co-infection caused by Streptococcus pneumoniae and HSV-1. Of note, beyond age, the patient had no known risk factors for both entities and recovered fully after antibiotic and antiviral therapy. This case underlines that clinicians must be aware of CNS co-infection despite being a rare diagnosis. This should be suspected particularly in patients who present an unusual clinical course of CNS infection.

Effect of Gardenia extract ZG on the adsorption quantity of herpes simplex virus type 1 (HSV-1)

To observe the effect of Gardenia extract ZG on the adsorption quantity of herpes simplex virus type 1 (HSV-1) so as to explore the mechanism of its antiviral activity, fluorescein isothiocyanate (FITC) was used as the fluorescent probe to label viruses and heparin sodium was used as control. Meanwhile , the effect of Gardenia extract ZG on the adsorption quantity on the surface of Hep-2 cells was determined by flow cytometry. It was demonstrated that adsorption of HSV-1 on the surface of Hep-2 cells exhibited the character of saturation and specificity and heparin sodium could prevent attachment of viruses on these cells. These results are in accord with those reported previously. It was also proved that the manner of drug-use prior to adsorption or simultaneous use of drug and adsorption was better than adsorption prior to drug-use, and the inhibition rates of the former and latter manner were 84. 76% and 82.92% respectively. Three manners of drug-use with Gardenia extract ZG were all effective to reduce the adsorption quantity of viruses, especially the manner of simultaneous use of drug and adsorption with an adsorption inhibition rate of 68.46% . From the above observation, it is apparent that the mechanism of anti-viral activity of Gardenia extract ZG may be via several steps involved in the HSV-1 adsorption.

Herpes simplex virus-1 infection or Simian virus 40-mediated immortalization of corneal cells causes permanent translocation of NLRP3 to the nuclei

AIM: To investigate into the potential involvement of pyrin containing 3 gene(NLRP3), a member of the nucleotide-binding oligomerization domain-like receptors with cytosolic pattern recognition, in the host defense of corneas against viruses.METHODS: The herpes viral keratitis model was utilized in BALB/c mice with inoculation of herpes simplex virus-1(HSV-1). Corneal tissues removed during therapy of patients with viral keratitis as well as a Simian vacuolating virus 40(SV40)-immortalized human corneal epithelial cell line were also examined.Immunohistochemistry was used to detect NLRP3 in these subjects, focusing on their distribution in tissue or cells. Western blot was used to measure the level of NLRP3 and another two related molecules in NLPR3 inflammasome, namely caspase-1 and IL-1β.RESULTS: The NLRP3 activation induced by HSV-1infection in corneas was accompanied with redistribution of NLRP3 from the cytoplasm to the nucleus in both murine and human corneal epithelial cells. Furthermore,in the SV40-immortalized human corneal epithelial cells,NLRP3 was exclusively located in the nucleus, and treatment of the cells with high concentration of extracellular potassium(known as an inhibitor of NLRP3activation) effectively drove NLRP3 back to the cytoplasm as reflected by both immunohistochemistry and Western blot.· CONCLUSION: It is proposed that herpes virus infection activates and causes redistribution of NLRP3 to nuclei. Whether this NLRP3 translocation occurs with other viral infections and in other cell types merit further study.

Antiviral activity of Basidiomycete mycelia against influenza type A(serotype H1N1) and herpes simplex virus type 2 in cell culture

In this study, we investigated the in vitro antiviral activity of the mycelia of higher mushrooms against influenza virus type A(serotype H1N1) and herpes simplex virus type 2(HSV-2), strain BH. All 10 investigated mushroom species inhibited the reproduction of influenza virus strain A/FM/1/47(H1N1) in MDCK cells reducing the infectious titer by 2.0–6.0 lg ID50. Four species, Pleurotus ostreatus, Fomes fomentarius, Auriporia aurea, and Trametes versicolor, were also determined to be effective against HSV-2 strain BH in RK-13 cells, with similar levels of inhibition as for influenza. For some of the investigated mushroom species—Pleurotus eryngii, Lyophyllum shimeji, and Flammulina velutipes—this is the first report of an anti-influenza effect. This study also reports the first data on the medicinal properties of A. aurea, including anti-influenza and antiherpetic activities. T. versicolor 353 mycelium was found to have a high therapeutic index(324.67), and may be a promising material for the pharmaceutical industry as an anti-influenza and antiherpetic agent with low toxicity. Mycelia with antiviral activity were obtained in our investigation by bioconversion of agricultural wastes(amaranth flour after CO2 extraction), which would reduce the cost of the final product and solve some ecological problems.

Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology

Human herpesviruses （HVs） have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system （CNS）. The ability of HVs to enter a state of latency, a defining char- acteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease （NDD） patholo- gy by highlighting two prominent members of the HV family, herpes simplex virus 1 （HSV-1） and human herpesvirus 6 （HHV-6）. We （i） introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then （ii） review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer＇s disease （AD） and multiple sclerosis （MS）, respectively. We then （iii） highlight and dis- cuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we （iv） discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.

A functional type I interferon pathway drives resistance to cornea herpes simplex virus type 1 infection by recruitment of leukocytes

Type I interferons are critical antiviral cytokines produced following herpes simplex virus type-1 （HSV-1） infection that act to inhibit viral spread. In the present study, we identify HSV-infected and adjacent uninfected corneal epithelial cells as the source of interferon-a. We also report mice deficient in the A1 chain of the type I IFN receptor （CDl18-/） are extremely sensitive to ocular infection with low doses （100 PFU） of HSV-1 as seen by significantly elevated viral titers in the cornea Compared to wild type （WT） controls. The enhanced susceptibil- ity correlated with a loss of CD4＋ and CD8＋ T cell recruitment and aberrant chemokine production in the cornea despite mounting an adaptive immune response in the draining mandibular lymph node of CDll8/ mice. Taken together, these results highlight the importance of IFN production in both the innate immune response as well as eliciting chemokine production required to facilitate adaptive immune cell trafficking.

The Herpes Simplex Virus Type 1 Multiple Function Protein ICP27

The herpes simplex virus type 1 (HSV-1) infected-cell protein 27 (ICP27) is an essential,highly conserved protein involved in various steps of HSV-1 gene regulation as well as in the shut-off of host gene expression during infection. It functions primarily at the post-transcriptional level in inhibiting precursor mRNA splicing and in promoting nuclear export of viral transcripts. Recently,many novel functions performed by the HSV-1 ICP27 protein were shown,including leptomycin B resistance,inhibition of the type Ⅰ interferon signaling,regulation of the viral mRNA translation and determining the composition of HSV-1 virions.

The Herpes Simplex Virus Type 1 Infected Cell Protein 22

As one of the immediate-early(IE)proteins of herpes simplex virus type 1(HSV-1),ICP22 is a multifunctional viral regulator that localizes in the nucleus of infected cells.It is required in experimental animal systems and some nonhuman cell lines,but not in Vero or HEp-2 cells.ICP22 is extensively phosphorylated by viral and cellular kinases and nucleotidylylated by casein kinase Ⅱ.It has been shown to be required for efficient expression of early(E)genes and a subset of late(L)genes.ICP22,in conjunction with the UL13 kinase,mediates the phosphorylation of RNA polymerase Ⅱ.Both ICP22 and UL13 are required for the activation of cdc2,the degradation of cyclins A and B and the acquisition of a new cdc2 partner,the UL42 DNA polymerase processivity factor.The cdc2-UL42 complex mediates postranscriptional modification of topoisomerase Ⅱα in an ICP22-dependent manner to promote L gene expression.In addition,ICP22 interacts with cdk9 in a Us3 kinase dependent fashion to phosphorylate RNA polymerase Ⅱ.

Feasibility of herpes simplex virus type 1 mutants labeled with radionuclides for tumor treatment

For over one hundred years, viruses have been recognized as capable of killing tumor cells. At present, people are still researching and constructing more suitable oncolytic viruses for treating different malignant tumors. Although extensive studies have demonstrated that herpes simplex virus type 1 (HSV-1) is the most potential oncolytic virus, therapies based on herpes simplex virus type 1 vectors still arouse bio-safety and risk management issues. Researchers have therefore introduced the new idea of treating cancer with HSV-1 mutants labeled with radionuclides, combining radionuclide and oncolytic virus therapies. This overview briefly summarizes the status and mechanisms by which oncolytic viruses kill tumor cells, discusses the application of HSV-1 and HSV-1 derived vectors for tumor therapy, and demonstrates the feasibility and prospect of HSV-1 mutants labeled with radionuclides for treating tumors.

Current Status of Natural Products from Plants as Anti-herpes Simplex Virus 1 Agents

Nucleoside analogues have been the mainstay of clinical treatment of herpes simplex virus 1 (HSV-1) infections since their development. However, the emergence of drug resistant strains has underlined the urgency of the discovery of novel anti-HSV-1 drugs. Natural products, which provided many novel drug leads, are known to be an important source of anti-HSV-1 agents. Herein, we present an overview of natural products with anti-HSV-1 activities isolated from a variety of plants reported in recent years. Several different compounds, mainly belonging to the three groups of polysaccharides, polyphenols and terpenes, showed antiviral effects against HSV-1, indicating their potential to be promising anti-HSV-1 agents.

DNA vaccine expressing herpes simplex virus 1 glycoprotein C and D protects mice against herpes simplex keratitis

AIM： To investigate whether DNA vaccine encoding herpes simplex virus 1（HSV-1） glycoprotein C（g C） and glycoprotein D（g D） will achieve better protective effect against herpes simplex keratitis（HSK） than DNA vaccine encoding gD alone. METHODS： DNA vaccine expressing gD or gC combined g D（g D.g C） were constructed and carried by chitosan nanoparticle. The expression of fusion protein gD and gC were detected in DNA/nanoparticle transfected 293 T cells by Western-blot. For immunization, mice were inoculated with DNA/nanoparticle for 3 times with 2 wk interval, and two weeks after the final immunization, the specific immune responses and clinical degrees of primary HSK were evaluated. RESULTS： Fusion protein g D.g C could be expressed successfully in cultured 293 T cells. And, p RSC-g C.g DIL21 DNA/chitosan nanoparticle could effectively elicit strongest humoral and cellular immune response in primary HSK mice evidenced by higher levels of specific neutralizing antibody and s Ig A production, enhanced cytotoxicities of splenocytes and nature killer cells（NK）,when compared with those of gD alone or mocked vaccine immunized mice. As a result, gC-based vaccine immunized mice showed least HSK disease. CONCLUSION： gC-based DNA vaccine could effectively prevent the progress of primary HSK, suggesting that this DNA vaccine could be a promising vaccine for HSK treatment in the future.

Analysis of the Cellular Localization of Herpes Simplex Virus 1 Immediate-early Protein ICP22

Nuclear proteins often form punctiform structures, but the precise mechanism for this process is unknown. As a preliminary study, we investigated the aggregation of an HSV-1 immediate-early protein, infected-cell protein 22 (ICP22), in the nucleus by observing the localization of ICP22-EGFP fusion protein. Results showed that, in high-level expression conditions, ICP22-EGFP gradually concentrates in the nucleus, persists throughout the cell cycle without disaggregation even in the cell division phase, and is finally distributed to daughter cells. We subsequently constructed a mammalian cell expression system, which had tetracycline- dependent transcriptional regulators. Consequently, the location of ICP22-EGFP in the nucleus changed with distinct induction conditions. This suggests that the cellular location of ICP22 is also influenced by promoter regulation, in addition to its own structure. Our findings provide new clues for the investigation of transcriptional regulation of viral genes. In addition, the non-protease reporter system we constructed could be utilized to evaluate the role of internal ribosome entry sites (IRES) on transcriptional regulation.

A Multiple Functional Protein:the Herpes Simplex Virus Type 1 Tegument Protein VP22

The herpes simplex virus type 1(HSV-1) VP22,is one of the most abundant HSV-1 tegument proteins with an average stoichiometry of 2 400 copies per virion and conserved among alphaherpesvirinae. Many functions are attributed to VP22,including nuclear localization,chromatin binding,microtubule binding,induction of microtubule reorganization,intercellular transport,interaction with cellular proteins,such as template activating factor I(TAF-I) and nonmuscle myosin II A(NMIIA) ,and viral proteins including tegument protein VP16,pUS9 and pUL46,glycoprotein E(gE) and gD. Recently,many novel functions performed by the HSV-1 VP22 protein have been shown,including promotion of protein synthesis at late times in infection,accumulation of a subset of viral mRNAs at early times in infection and possible transcriptional regulation function.

PNKP Knockdown by RNA Interference Inhibits Herpes Simplex Virus-1 Replication in Astrocytes

Herpes simplex virus-1 (HSV-1) is a major pathogen that causes various central nervous system (CNS) diseases,including herpes simplex encephalitis and meningitis.According to recent studies,PNKP significantly affects the proliferation of HSV-1 in astrocytes.Here,we used viral proliferation curves to confirm the significant inhibitory effects of PNKP on HSV-1 proliferation.PNKP downregulation was also confirmed by analyzing the transcription of viral genes.We found that PNKP downregulation affects the viral DNA copy number.This study preliminarily confirms that PNKP affects viral proliferation by affecting HSV-1 genome cyclization.These results also suggest that astrocytes play a specific role in preventing HSV-1 infection.

Preliminary study on Herpes simplex virus type 1 infection of human oral epithelial cell in vitro

Objective： To explore the functions and mechanisms of herpes simplex virus type I（HSV-1） while infecting human oral epithelial cells in vitro（being similar to the infection in vivo）. Methods：An abundance of HSV-1 strains amplified in Vero cells were used to infect human oral epithelial cells. The culture supernatant was collected to infect Vero cells again. Morphology of HSV-1 was identified by inverted microscope and transmission electron microscope. Nucleic acid of the virus was detected by PCR. Results：The infected human oral epithelial cells didn＇ t display an obvious cytopathic effect（CPE） under inverted microscope（while Vero cells which were infected by the culture supernatant showed typical（CPE）. The virus particles were not observed in the cytoplasm nor in nucleus of human oral epithelial cells, however under transmission electron microscope in the cytoplasm of Vero cells, the nucleic acid of HSV-1 could be detected in infected human oral epithelial cells, by PCR. Conclusion-HSV-1 can successfully infect human oral epithelial cells. This model may provide a useful approach for studying the pathogenesis of herpes virus-associated periodontal disease.

Herpes Simplex Virus Type 1 ICP27 Protein:Its Expression, Purification and Specific Antiserum Production

Herpes simplex virus type 1 (HSV-1) is the causative agent of cold sores and other more serious diseases. HSV-1 infected-cell protein 27 (ICP27) is an immediate-early regulatory phosphoprotein homologous to gene products identified in all classes of herpesviruses so far. To raise the antiserum to ICP27 for further characterization of its biological function, the ICP27 gene was cloned into the pET-28a (+) vector, then ICP27 protein was expressed in E. coli and purified by nickel-nitrilotriacetic acid (Ni 2+ -NTA) affinity resin column, finally the purified protein was used to raise antiserum. Western blot analysis demonstrated that the antiserum recognized the recombinant protein, and the antiserum was able to probe the ICP27 in HSV-1 infected cells with high specificity by immunofluorescence assay (IFA). Therefore, the specific antiserum will provide a valuable tool for further studies investigating ICP27's biological function during HSV-1 infection.

Herpes simplex virus type 1 in peptic ulcer disease: An inverse association with Helicobacter pylori

AIM: To assess the frequency of herpes simplex virus type Ⅰ in upper gastrointestinal tract ulcers and normal mucosa with the modern and better assays and also with a larger number of well characterized patients and controls and its relationship to Helicobacter pylori(H pylori).METHODS: Biopsy specimens from 90 patients (34 with gastric ulcer of the prepyloric area and 56 with duodenal ulcer) were evaluated. Biopsies from 50 patients with endoscopically healthy mucosa were considered as the control group. The method used to identify herpes simplex virus-1 (HSV-1) was polymerase chain reaction.H pylori was detected by the CLO-test and by histological method.RESULTS: Herpes simplex virus-1 was detected in 28 of 90 patients with peptic ulcer (31%) [11 of 34 patients with gastric ulcer (32.4%) and 17 of 56 with duodenal ulcer (30.4%)] exclusively close to the ulcerous lesion.All control group samples were negative for HSV-1.The likelihood of H pylori negativity among peptic ulcer patients was significantly higher in HSV-1 positive cases than in HSV-1 negative cases (P = 0.009). Gastric ulcer patients with HSV-1 positivity were Strongly associated with an increased possibility of Helicobacter pylori negativity compared to duodenal ulcer patients (P= 0.010).CONCLUSION: HSV-1 is frequent in upper gastrointestinal tract ulcers but not in normal gastric and duodenal mucosa. There is an inverse association between HSV-1 and H pylori infection.

HISP-1 Inhibits HSV-1 Infection in Cultured Vero Cells

Herpes simplex virus-1 (HSV-1) remains a leading cause of viral disease worldwide and is spread by direct contact with infected lesions. There is no vaccine against HSV-1 infections and there remains a need to identify therapeutics that could reduce the spread. In this study various hispolon compounds were analyzed to determine their antiviral potential against HSV-1 infections in cultured Vero cells. To determine the effects on infectivity and possible mechanisms of inhibition, the following assays were conducted. In vitro cytotoxicity assays were conducted to determine the effect of the compounds on cell viability and the maximum non-cytotoxic concentrations. Antiviral assays measured cell viability, percent inhibition of infection following treatment with the compounds, and the effect on the viral infection cycle. These effects were visualized using inverted light and fluorescent microscopy. Of the 24 hispolons tested, only hispolon pyrazole-1 (HISP-1) demonstrated antiviral effects. HISP-1 was demonstrated to effect early stages in HSV-1 infection in cultured Vero cells (attachment, penetration, and post-penetration). In silico modeling analyses were conducted to analyze the interactions between HISP-1 and viral glycoprotein D (gD). HISP-1 is safe at concentrations tested and is effective in inhibiting infection of HSV-1 in cultured cells. HISP-1 has potential for therapeutic use as an antiviral against HSV-1 infection, could work in synergy with other antivirals that work be a different modality, and could be developed as a component of a topical agent to reduce the spread of HSV-1 infections.

Enhanced Disinfection Effect of a Compound Disinfectant against Bovine Herpes Virus Type 1 at Low Temperature

A compound disinfectant, which consisted of didecyldimethylammonium chloride (DDAC), ortho-dichlorobenzene (1,2-dichlorobenzene, ODB), and chlorocresol (4-chloro-3-methylphenol, CC), and its component chemicals were individually tested for effectiveness against bovine herpes virus type 1 (BHV-1). DDAC, DDAC+ODB, DDAC+CC, and DDAC+ODB+CC showed effectiveness against BHV-1 at room temperature. However, ODB, CC, and ODB+CC showed no virucidal effects. The effects of all disinfectants tested were decreased at low temperature. DDAC showed disinfectant effects at a dilution of 1/800 and DDAC+ODB, DDAC+CC, and DDAC+ODB+CC at dilutions of 1/800 and 1/1600 at low temperature in the presence of 2% fetal bovine serum (FBS) but ODB, CC, and ODB+CC showed no virucidal effects. At low temperature and in the presence of 10% FBS, DDAC, DDAC+ODB, and DDAC+CC showed disinfectant effects at dilutions of 1/800, whereas ODB, CC, and ODB+CC showed no virucidal effects. DDAC+ ODB+CC was more effective (at 1/800 and 1/1600) than the other disinfectants under these conditions. In conclusion, a combination of three disinfectant components (DDAC+ODB+CC), enhanced the disinfectant effects at low temperature and in organic matter contamination.